U.S. patent application number 15/420733 was filed with the patent office on 2017-11-16 for genotype- or phenotype-based drug formulations.
This patent application is currently assigned to BAYER AKTIENGESELLSCHAFT. The applicant listed for this patent is BAYER AKTIENGESELLSCHAFT. Invention is credited to Kristin DICKSCHEN, Thomas El ING, Stefan WILLMANN.
Application Number | 20170326080 15/420733 |
Document ID | / |
Family ID | 48520964 |
Filed Date | 2017-11-16 |
United States Patent
Application |
20170326080 |
Kind Code |
A1 |
WILLMANN; Stefan ; et
al. |
November 16, 2017 |
Genotype- or Phenotype-Based Drug Formulations
Abstract
The invention relates to a combination of two or more
pharmaceutically active substances, of which at least one is a
metabolic product ("metabolite") of the other ("parent substance"),
wherein in particular the dosages thereof are selected such that
genotypically or phenotypically related variability in the
conversion of the parent substance to the metabolite in particular
individuals is compensated for.
Inventors: |
WILLMANN; Stefan;
(Dusseldorf, DE) ; El ING; Thomas; (Langenfeld,
DE) ; DICKSCHEN; Kristin; (Dusseldorf, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
BAYER AKTIENGESELLSCHAFT |
Leverkusen |
|
DE |
|
|
Assignee: |
BAYER AKTIENGESELLSCHAFT
Leverkusen
DE
|
Family ID: |
48520964 |
Appl. No.: |
15/420733 |
Filed: |
January 31, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14403823 |
Nov 25, 2014 |
|
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PCT/EP2013/060824 |
May 27, 2013 |
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15420733 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
G16B 5/00 20190201; A61K 31/138 20130101; A61P 43/00 20180101; A61P
15/08 20180101; A61K 31/138 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/138 20060101
A61K031/138; G06F 19/12 20110101 G06F019/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 1, 2012 |
EP |
12170401.9 |
Claims
1. Method for preparing a fixed-dose combination pharmaceutical
formulation, the fixed-dose combination pharmaceutical formulation
comprising a parent substance, the action of which is dependent on
the quantity or the activity of expressed protein variants, enzyme
variants, receptor variants or transporter variants, and at least
one metabolite thereof, and the method comprising the following
steps: a) inputting into an input module of an organism, of its
genotype or phenotype, of a parent substance and at least one
metabolite of the parent substance, of an optimal reference
steady-state plasma level for the parent substance for a reference
genotype or reference phenotype in the case of delivery of the
parent substance alone, b) forwarding of the data from a) into a
calculation module comprising a substance data module, an organism
data module, a genotype data module or phenotype data module, and a
physiologically based pharmacokinetic model, wherein the substance
data module comprises data concerning the physicochemical and/or
biochemical properties of the substance, the organism module
comprises data concerning the compartments of the organism, and the
genotype data module or phenotype data module comprises genotype-
or phenotype-specific data, c) automatically selecting parent
substance and metabolite-specific data from the substance data
module, d) automatically selecting organism-specific data from the
organism data module on the basis of input a), e) automatically
selecting genotype-specific or phenotype-specific data from the
genotype data module or phenotype data module, f) forwarding of the
selected data from a) to e) into the physiologically based
pharmacokinetic model, g) calculating, by means of the
physiologically based pharmacokinetic model, an optimized dosage
for the parent substance for the reference genotype or reference
phenotype in order to attain the inputted optimal reference plasma
level for the parent substance from a), h) calculating the
reference steady-state plasma level for the metabolites for the
reference genotype or reference phenotype in the case of
administration of the dose of parent substance calculated in g), i)
calculating a plasma level of the metabolites that is reduced owing
to the genotype or phenotype with respect to the corresponding
reference plasma level in the case of administration of the dose of
parent substance calculated in g), j) calculating a metabolite dose
and a parent substance dose for the combined attainment of the
reference plasma level for the metabolites from h) and of the
reference plasma level for the parent substance from a), k)
outputting the metabolite dose and the parent substance dose for
the fixed-dose combination pharmaceutical formulation via an output
module, and/or forwarding the dose calculated in j) into an
automated device for dosing medicaments.
2. Method according to claim 1, wherein the dosage is defined in a
genotype- or phenotype-specific manner.
3. Method according to claim 1, wherein the formulation comprises
tamoxifen and endoxifen.
4. Method according to claim 3, wherein the formulation comprises
15-25 mg of tamoxifen and 0.25-5.0 mg of endoxifen.
5. Method according to claim 4, wherein the formulation is adapted
for CYP2D6 IM patients and comprises 15-25 mg of tamoxifen and
0.25-2.00 mg of endoxifen.
6. Method according to claim 4, wherein the formulation is adapted
for CYP2D6 PM patients and comprises 15-25 mg of tamoxifen and
1.0-5.0 mg of endoxifen.
Description
[0001] The invention relates to a combination of two or more
pharmaceutically active substances, of which at least one is a
metabolic product ("metabolite") of the other ("parent substance"),
in particular the dosages thereof are selected such that
genotypically or phenotypically (definition of genotype
http://de.wikipedia.org/wiki/Genotyp, definition of phenotype:
http://de.wikipedia.org/wiki/Ph%C3%A4notyp) related variability in
the conversion of the parent substance to the metabolite(s) in
particular individuals is compensated for. The invention further
relates to a combination of two or more pharmaceutically active
substances, of which at least one is a metabolic product of the
other, and the dosages thereof are selected such that genotypically
or phenotypically related variability in transporters, receptors or
other proteins involved in pharmacokinetic or pharmacodynamic
processes of the parent substance and of the metabolite(s) in
particular individuals is compensated for.
[0002] The principle according to the invention will be illustrated
using the example of the combination of the breast cancer
medicament tamoxifen and its active metabolite endoxifen.
[0003] In pharmacotherapy, there are numerous examples of
pharmaceuticals, the pharmacological action of which arises from
the interplay of the administered parent substance with metabolites
which develop in the body of the patient. Such so-called active
metabolites are generally formed via enzymatically catalysed
processes, which can take place in, for example, the liver, the
kidneys, the intestine or any other organ of the body. The activity
of these enzymatic processes can widely differ in different
individuals. The reasons for enzyme activities differing from
individual to individual are diverse in nature. Firstly, there are
individual variations in the quantity of the expressed enzyme
variants which can be brought about by, for example, enzyme
inhibitors or inducers or else genetic causes. Secondly, there are
individual variations in the activity of the expressed enzyme
variants which can occur owing to, for example, enzyme inhibitors
or inducers or else genetic causes. Many active pharmaceutical
ingredients are known cytochrome P450 enzyme inhibitors, for
example: [0004] 2-(4-chlorophenoxy)ethanol, acarbose, acebutolol,
acenocoumarol, acetazolamide, adefovir, ademetionine, ajmaline,
albendazole, alitretinoin, allopurinol, alosetron, ambroxol,
amphetamine, amiloride, aminoglutethimide, aminophenazone,
amiodarone, amitriptyline, amlodipine, amodiaquine, amprenavir,
anastrozole, androstandolone, aprepitant, aripiprazole, arsenic
trioxide, artemisinin, artesunate, astemizole, atazanavir,
atomoxetine, atorvastatin, atovaquone, atropine, azapropazone,
azelastine, azithromycin, barnidipine, benazepril, benidipine,
benzbromarone, benzethonium, benzocaine, bergapten, betamethasone,
betaxolol, bezafibrate, bicalutamide, bifonazole, biperiden,
bortezomib, bromazepam, bromocriptine, brompheniramine, budipine,
buprenorphine, buproprion, calcitriol, candesartan, capecitabine,
carbamazepine, carbinoxamine, carteolol, caspofungin, celecoxib,
cerivastatin, quinidine, quinine, chloramphenicol, chlormadinone,
chloroquine, chlorphenamine, chlorpromazine, chlorzoxazone,
ciclosporin, cimetidine, ciprofibrate, ciprofloxacin, cisapride,
cisplatin, citalopram, clarithromycin, clemastine, clevidipine,
clindamycin, clobetasol, clofazimine, clofenotane, clofibrate,
clomethiazole, clomifene, clomipramine, clonazepam, clopidogrel,
clotiazepam, clotrimazole, clozapine, cocaine, codeine, caffeine,
colchicine, colecalciferol, cyclizine, cylcophosphamide,
cyproterone, dacarbazine, dactinomycin, dalfopristine, danazol,
dantrolene, daunorubicin, deferoxamine, delarvirdine, desipramine,
desloratadine, desvenlafaxine, dexamethasone, dexamfetamine,
dexfenfluramine, dexibuprofen, dextrometorphan, dextropropoxyphene,
diazepam, diclofenac, dicoumarol, dihydralazine, dihydroergotamine,
diiodohydroxypropane, diltiazem, dimethyl sulphoxide,
dimetotiazine, diosmectite, diosmin, diphenhydramine, disulfiram,
docetaxel, dolasetron, dopamine, doxepin, doxorubicin, doxycycline,
ebastine, econazole, efavirenz, emetine, enoxacin, enoxolone,
enprostil, entacapone, epinastine, epinephrine, eplerenone,
eprosartan, ergometrine, ergotamine, erythromycin, escitalopram,
estriol, etanautine, ethanol, ethinylestradiol, ethotoin, etodolac,
etomidate, etoposide, etoricoxib, etretinate, exemestane,
ezetimibe, felbamate, felodipine, fenfluramine, fenofibrate,
fentanyl, fexofenadine, flecainide, flumequine, fluorouracil,
fluoxetine, fluphenazine, flurazepam, flurbiprofen, flurithromycin,
flutamide, fluvastatin, fluvoxamine, fomepizole, formestane,
fosamprenavir, fosphenytoin, gefitinib, gemfibrozil, glibenclamide,
gliclazide, glucose, glutethimide, granisetron, g-strophanthin,
halofantrine, haloperidol, histamine, hydralazine, hydrocortisone,
hydroxycarbamide, hydroxychloroquine, hydroxyzine, ibuprofen,
idarubicin, ifosfamide, imatinib, imipramine, indinavir,
indometacin, insulin, ipriflavone, irbesartan, irinotecan,
isoconazole, isoflurane, isoniazid, isoprenaline, isopropanol,
isosorbide dinitrate, isradipine, itraconazole, josamycin,
ketoconazole, ketoprofen, labetalol, lafutidine, lansoprazole,
leflunomide, lentinan, lercarnidipine, letrozole, levofloxacin,
levomepromazine, levonorgestrel, lidocaine, lomefloxacin,
lomustine, loperamide, lopinavir, loratadine, lornoxicam, losartan,
lovastatin, manidipine, masoprocol, meclozine, medazepam,
medroxyprogesterone, medrysone, mefenamic acid, mefloquine,
meglutol, melatonin, meloxicam, melperone, memantine, menadione,
mephenytoin, mequitazine, mesuximide, metamfetamine, metformin,
methadone, methazolamide, methoxsalen, methylphenidate,
methylphenobarbital, methylprednisolone, metoclopramide,
metoprolol, metronidazole, metyrapone, mexiletine, mianserin,
mibefradil, miconazole, midazolam, midecamycin, midodrine,
mifepristone, minoxidil, miocamycin, mirtazapine, mitoxantrone,
mizolastine, moclobemide, modafinil, mometasone, montelukast,
moracizine, nefazodone, nelfinavir, neostigmine, nevirapine,
nicardipine, niclosamide, nicotinamide, nifedipine, nicotine,
nicotic acid, nilutamide, nilvadipine, nimesulide, nisoldipine,
nitrendipine, nitroprusside, norepinephrine, norfloxacin,
nortriptyline, noscapine, octopamine, ofloxacin, olanzapine,
oleandomycin, omeprazole, ondansetron, orphenadrine, oxamniquine,
oxatomide, oxcarbazepine, oxprenolol, oxybutynin, oxycodone,
paclitaxel, pancreozymin (cholecystokinin), pantoprazole,
paracetamol, parecoxib, pargyline, paroxetine, pazopanib,
pefloxacin, pentoxyverin, perazine, pergolide, perhexiline,
perphenazine, phenazone, phenelzine, phenobarbital, phensuximide,
phentermine, phenylbutazone, phenylpropanolamine, phenytoin,
physostigmine, pilocarpine, pimozide, pindolol, pioglitazone,
piroxicam, pranlukast, prasterone, pravastatin, praziquantel,
prednisolone, prednisone, primaquine, pristinamycin, probenecid,
progesterone, proguanil, promethazine, propafenone, propanol,
propiverine, propofol, propranolol, pyrimethamine, quassia,
mercury, quetiapine, quinidine, quinine, quinupristin, rabeprazole,
raloxifene, ranitidine, reboxetine, retinol, rifampicin,
risperidone, ritonavir, rivastigmine, rofecoxib, rokitamycin,
ropinirole, rosiglitazone, rosuvastatin, roxithromycin, rutoside,
salbutamol, salicylamide, salmeterol, saquinavir, selegiline,
seratrodast, sertaconazole, sertraline, sildenafil, silymarin,
simvastatin, sirolimus, somatostatin, sorbitol, sparteine,
spironolactone, nitrogen monoxide, sulconazole, sulfadiazine,
sulfadimethoxine, sulfadimidine, sulfafurazole, sulfamethizole,
sulfamethoxazole, sulfamoxole, sulfanilamide, sulfaphenazole,
sulfapyridine, sulfinpyrazone, sulindac, sulpiride, suprofen,
tacrolimus, tamoxifen, tegaserod, telithromycin, telmisartan,
temafloxacin, teniposide, tenofovir, terbinafine, terconazole,
terfenadine, teriparatide, testosterone, tetracycline,
theophylline, thiamazole, thiopental, thioridazine, thiosulphate,
thiotepa, tiabendazole, tibolone, ticlopidine, timolol, tinidazole,
tioconazole, tiopronin, tiotixen, tocainide, tocopherol, tofisopam,
tolbutamide, tolcapone, topiramate, topotecan, torasemide,
tramadol, tranylcypromine, trastuzumab, treosulfan, tretinoin,
triamterene, triazolam, trichloroethylene, triclosan, trimethoprim,
tripelennamine, triprolidine, troglitazone, troleandomycin,
tropisetron, trospium, ursodeoxycholic acid, valdecoxib, valproic
acid, valsartan, venlafaxine, verapamil, vinblastine, vincristine,
vinorelbine, virginiamycin, voriconazole, vorozole, warfarin,
yohimbine, zafirlukast, ziprasidone, zolpidem, zonisamide.
[0005] Particular emphasis is given here to: fluvoxamine,
ciprofloxacin, gemfibrozil, bupropion, cinacalcet, fluoxetine,
paroxetine, quinidine, indinavir, nelfinavir, ritonavir,
clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir,
telithromycin, trimethoprim, amiodarone, duloxetine, sertraline,
terbinafine, aprepitant, erythromycin, verapamil, diltiazem,
cimetidine, amiodarone
[http://medicine.iupui.edu/clinpharm/ddis/table.aspx as of May 9,
2012].
[0006] Known inhibitors of phase 2 enzymes are, inter alia: [0007]
acarbose, acetylcholine, acetylsalicylic acid, amitriptyline,
apomorphine, artemisinin, ascorbic acid, bendroflumethiazide,
bergapten, bromocriptine, carbachol, carbamazepine, carmustine,
celecoxib, chenodeoxycholic acid, quinine, chlorhexidine,
chloroquine, cimetidine, clomipramine, clonidine, cocaine,
cortisone, dactinomycin, desipramine, diazepam, dicoumarol,
dicycloverine, diosmin, disulfiram, doxepin, enoxolone, entacapone,
estradiol, etacrynic acid, fluconazole, fluphenazine, folic acid,
haloperidol, hematin, hydrocortisone, hymecromone, ibuprofen,
imipramine, indometacin, iproniazid, ketoprofen, lidocaine,
lopinavir, medroxyprogesterone, melatonin, mepacrine, mercaptamine,
mersalyl, mesalazine, methyldopa, moclobemide, naproxen, sodium
citrate, sodium salicylate, niflumic acid, nicotine, olsalazine,
oxedrine, paclitaxel, pargyline, phenylbutazone, physostigmine,
pipamperone, polihexanide, primaquine, probenecid, progesterone,
propylthiouracil, pyridoxal, pyridoxine, pyrimethamine, ranitidine,
ritonavir, salicylamide, salicylic acid, saquinavir, silymarin,
sulphobromophthalein, sulindac, tacrine, tamoxifen, tetracycline,
thiomersal, tolcapone, triclosan, tubocurarine, vecuronium,
warfarin, hydrogen peroxide.
[0008] Examples of known cytochrome P450 enzyme inducers are:
[0009] 2-(4-chlorophenoxy)ethanol, acarbose, acetylsalicylic acid,
acriflavinium chloride, albendazole, aldosterone, alum,
aminoglutetimide, aminosalicylic acid, amobarbital,
angiotensinamide, aprepitant, aprobarbital, aripiprazole,
artemisinin, ascorbic acid, azatidine, beclometasone, benoxaprofen,
beta-carotene, betamethasone, bexarotene, bezafibrate, biotin,
bosentan, bucladesine, buserelin, captopril, carbamazepine,
carbamide, carboplatin, quinidine, quinine, chlordiazepoxide,
chlorothiazide, chlorpromazine, ciclosporin, ciprofibrate,
ciprofloxacin, cisplatin, calcitriol, clarithromycin, clofenotane,
clofibrate, clomifen, clonazepam, clonidine, clotrimazole,
clozapine, colchicine, colestyramine, corticotropin, cyclobarbital,
cyclophosphamide, dapsone, daunorubicin, dexamethasone,
dextropropoxyphene, diazepam, dibutyl phthalate, diclofenamide,
dicloxacillin, dicycloverine, diethyl ether, diethylstilbestrol,
diiodohydroxypropane, dinoprostone, diosmectite, diosmin,
docetaxel, doxorubicin, doxylamine, efavirenz, eletriptan,
enoxacin, ergocalciferol, erythromycin, estriol, ethanol,
ethinylestradiol, etoposide, fenbendazole, felbamate, fluconazole,
flucloxacillin, flufenamic acid, fluorescein, fluvastatin,
gemfibrozil, glucose, glutathione, glycerol, glycyrrhizic acid,
granisetron, griseofulvin, guanethidine, haloperidol, histamine,
hydrocortisone, hydroxycarbamide, ifosfamide, insulin, ipriflavone,
isoflurane, isoniazid, isoprenaline, isopropanol, itraconazole,
ketoconazole, cocaine, lansoprazole, lindane, loratadine,
lovastatin, lynestrenol, mebendazole, mecamylamine,
medroxyprogesterone, metamizole, methadone, metharbital,
methohexital, methylprednisolone, methyltestosterone,
metoclopramide, metyrapone, mifepristone, mirtazapine,
mitobronitol, mitomycin, mitotane, moclobemide, modafinil, sodium
chloride, sodium salicylate, nelfinavir, nevirapine, nicardipine,
nicotinamide, nifedipine, nicotine, nitrazepam, norethisterone,
omeprazole, ondansetron, oxcarbazepine, oxiconazole, oxolamine,
oxomemazine, paclitaxel, pantoprazole, paracetamol, permethrin,
pethidine, phenobarbital, phenoxymethylpenicillin, phentermine,
phenylbutazone, phenylephrine, phenytoin, pindolol, pioglitazone,
pipamperone, pleconaril, prednisolone, prednisone, primaquine,
primidone, pristinamycin, probenecid, progesterone,
propylthiouracil, pyridostigmine, pyridoxine, mercury, quinine,
rabeprazole, reboxetine, reserpine, retinol, rifabutin, rifampicin,
rifapentine, rifaximin, ritonavir, rofecoxib, salicylic acid,
secobarbital, seratrodast, silymarin, spironolactone, streptozocin,
sulfadimidine, sulfinpyrazone, tamoxifen, temozolomide,
terbinafine, terfenadine, testosterone, tetrabenazine,
tetramethrin, thalidomide, thiamine, thiram, tiabendazole, tienilic
acid, tocopherol, topiramate, topotecan, tretinoin, triamcinolone
acetonide, triamcinolone, troglitazone, tryptophan, ursodeoxycholic
acid, valproic acid, verapamil, vinblastine, virginiamycin,
voglibose.
[0010] Particular emphasis is given here to: modafinil, nafcillin,
omeprazole, phenobarbital, phenytoin, rifampin, secobarbital,
carbamazepine, norethindrone, prednisone, rifampicin,
dexamethasone, isoniazid, efavirenz, nevirapine, barbiturates,
glucocorticoids, oxcarbazepine, pioglitazone, rifabutin,
troglitazone [http://medicine.iupui.edu/clinpharm/ddis/table.aspx
as of May 9, 2012].
[0011] The known inducers of phase 2 enzymes include, inter alia:
[0012] acetylcholine, acetylsalicylic acid, adenosine, amfetamine,
aminophylline, androstanolone, angiotensinamide, argatroban,
ascorbic acid, benfluorex, beta-carotene, betamethasone,
bucladesine, calcitriol, carbamazepine, chlorambucil,
chlorphenamine, cisapride, cisplatin, clofibrate, clozapine,
cocaine, corticotropin, desipramine, dexamethasone, dexamfetamine,
diazepam, diclofenac, diethylcarbamazine, diethyl ether,
dinoprostone, disulfiram, doxorubicin, entacapone, epinephrine,
esketamine, estradiol, estriol, ethanol, flunarizine, fluoxetine,
gabapentin, glyceryl trinitrate, glycine, g-strophantin,
hydralazine, hydrocortisone, hymecromone, ibuprofen, imipramine,
indometacin, insulin, isoprenaline, ketamine, lamotrigine,
levetiracetam, levodopa, lindane, melatonin, melphalan, mequinol,
metamizole, methionine, methotrexate, metoclopramide, nabumetone,
nandrolone, norepinephrine, olanzapine, paracetamol, pargyline,
phenobarbital, phenytoin, pipamperone, progesterone, promegestone,
propylthiouracil, retinol, rofecoxib, spironolactone, nitrogen
monoxide, sulindac, sultiame, tamoxifen, testosterone,
theophylline, tiadenol, tibolone, tioguanine, triamcinolone,
trimethoprim, troglitazone, valproic acid, verapamil, warfarin,
hydrogen peroxide.
[0013] [http://bioinformatics.charite.de/supercyp as of Apr. 24,
2012]. Besides active pharmaceutical ingredients, dietary
components may also have inhibitory and/or inducing effects on
enzymes, transporters, receptors or other proteins.
[0014] Known examples thereof are, inter alia: broccoli, grilled
meat, St John's wort, tobacco smoke, cheese, red wine, grapefruit
juice, folic acid, vitamin K, vitamin E, vitamin B6 and St John's
wort [Grober, U. (2009) "Interaktionen Arzneimittel and
Mikronahrstoffe fur die Kitteltasche [Interactions: Pharmaceuticals
and Micronutrients (Pocket Guide)]" Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart; Wentworth, J. M., M. Agostini,
et al. (2000). "St John's wort, a herbal antidepressant, activates
the steroid X receptor." J Endocrinol 166(3): R11-16.,
http://medicine.iupui.edu/clinpharm/ddis/table.aspx as of May 9,
2012]. Similar to the inducing effect of grilled meat on cytochrome
P450 1A1 (CYP1A1), the enzyme can also be induced by polycyclic
aromatics, which are present in cigarette smoke. For instance, it
is described in the literature that the activity of CYP1A1 in the
lungs, liver and intestine of smokers is increased in proportion to
their cigarette consumption Kzekaj, P., A. Wiaderkiewicz, et al.
(2005). "Tobacco smoke-dependent changes in cytochrome P450 1A1,
1A2, and 2E1 protein expressions in fetuses, newborns, pregnant
rats, and human placenta." Arch Toxicol 79(1): 13-24.; Fontana, R.
J., K. S. Lown, et al. (1999). "Effects of a chargrilled meat diet
on expression of CYP3A, CYP1A, and P-glycoprotein levels in healthy
volunteers." Gastroenterology 117(1): 89-98.; Kim, J. H., M. E.
Sherman, et al. (2004). "Expression of cytochromes P450 1A1 and 1B1
in human lung from smokers, non-smokers, and ex-smokers." Toxicol
Appl Pharmacol 199(3): 210-219., Pelkonen, O., M. Pasanen, et al.
(1986). "The effect of cigarette smoking on 7-ethoxyresorufin
O-deethylase and other monooxygenase activities in human liver:
analyses with monoclonal antibodies." Br J Clin Pharmacol 22(2):
125-134.; Zevin, S. and N. L. Benowitz (1999). "Drug interactions
with tobacco smoking. An update." Clin Pharmacokinet 36(6):
425-438.].
[0015] Furthermore, the pharmacological action of the parent
substance and its metabolite(s) may also be dependent on the
quantity or the activity of expressed protein variants, receptor
variants or transporter variants, which may likewise greatly differ
from individual to individual or within an individual owing to
inhibition or induction or genetic causes.
[0016] Examples of transporter inducers are: dexamethasone,
doxorubicin, flavonoids, St John's wort, phenobarbital, phenytoin,
rifampicin, vinblastine.
[0017] Examples of transporter inhibitors are: [0018] rifampicin,
cyclosporin A, gemfibrozil, lopinavir, ritonavir, clarithromycin,
furosemide, indometacin, probenecid, naproxen, ibuprofen,
piroxicam, acetylsalicylic acid, paracetamol, phenacetin,
ketoprofen, enalapril, bumetanide, cefoperazone, azathioprine,
methotrexate, valproate, flufenamate, phenylbutazone, levofloxacin,
dexamethasone, cytarabine, ampicillin, amoxicillin, ciclacillin,
cephalexin, cefadroxil, cephradine, cefdinir, ceftibuten, cefixime,
captopril, amiodarone, quinidine, lidocaine, itraconazole,
ketoconazole, diltiazem, felodipine, nicardipine, nifedipine,
nitrendipine, verapamil, indinavir, nelfinavir, saquinavir,
ethinylestradiol, norgestrel, progesterone, testosterone,
tacrolimus, erythromycin, mifepristone, paroxetine, talinolol,
tamoxifen, terfenadine, trifluoperazine, vincristine.
[0019] [Shitara, Y. (2011). "Clinical importance of OATP1B1 and
OATP1B3 in drug-drug interactions." Drug Metab Pharmacokinet 26(3):
220-227.; Van Aubel, R. A., R. Masereeuw, et al. (2000). "Molecular
pharmacology of renal organic anion transporters." Am J Physiol
Renal Physiol 279(2): F216-232.;
http://www.pharmazeutische-zeitung.de/index.php?id=2381].
[0020] Of particular importance to pharmacotherapy are those
differences in protein activity which have a genetic cause. As a
result of sequence variations
(http://de.wikipedia.org/wiki/Polymorphismus) in the alleles and/or
as a result of a varying number of alleles present, it is possible
for different variants and/or quantities of a protein to be
expressed. Both, the expressed variant and the expressed quantity
of a protein, can have a strong influence on the activity of the
protein variant.
[0021] In the literature, a well studied example of a polymorphic
protein is cytochrome P450 2D6 (CYP2D6), an enzyme for which it is
known that there is a multiplicity of different gene variants which
can be classified into four different phenotypes. The customary
designations for this purpose are: PM="poor metabolizer",
IM="intermediate metabolizer", EM="extensive metabolizer" and
UM="ultrarapid metabolizer" Vanger, U. M., J. Fischer, et al.
(2001). "Comprehensive analysis of the genetic factors determining
expression and function of hepatic CYP2D6." Pharmacogenetics 11(7):
573-585.].
[0022] Besides CYP2D6, there are numerous other polymorphic enzymes
from the class of cytochrome P450 (CYP) isoenzymes: [0023] CYP1A1,
CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C11,
CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP2W1,
CYP3A4, CYP3A5, CYP3A7, CYP3A43, CYP4A11, CYP4B1, CYP4F2, CYP4F22,
CYP7A1, CYP4B1, CYP7B1, CYP8A1, CYP8B1, CYP11A, CYP11B1, CYP11B2,
CYP17A, CYP19A, CYP21A, CYP24A, CYP26A1, CYP26B, CYP27A, CYP27B,
CYP46A, CYP51A.
[0024] Particular emphasis is given here to: CYP1A2, CYP2B6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7
[http://bioinformatics.charite.de/supercyp as of Apr. 24, 2012;
Tamaki, Y., T. Arai, et al. (2011). "Association between cancer
risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1,
SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in
Japan." Drug Metab Pharmacokinet 26(5): 516-522.].
[0025] There are similarly numerous polymorphic phase 2 enzymes or
other enzymes in metabolism, for example: [0026]
N-acetyltransferase 2 (NAT2), thiopurine S-methyltransferase
(TPMT), uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1,
UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10,
UGT2A1, UGT2A2, UGT2A3, UGT2B4, UGT2B7, UGT2B10, UGT2B15, UGT2B17,
sulfotransferase (SULT) 1A1, SULT1A2, SULT1A3, SULT1E1, SULT2A1,
SULT2B1, SULT4A1, glutathione S-transferase (GST) A1, GSTA2, GSTA3,
GSTA4, GSTA5, GSTM1, GSTM2, GSTM3, GSTM4, GSTM5, GSTP1, GSTT1,
GSTT2, GSTO1, GSTO2, catechol-o-methyltransferase (COMT),
flavin-dependent monooxygenase 3 (FMO), dihydropyrimidine
dehydrogenase (DPD), methylenetetrahydrofolate reductase
(MTHFR).
[0027] Particular emphasis is given here to: NAT2, TPMT, UGT1A1,
UGT1A4, UGT2B7, UGT2B15, SULT1A1, SULT1A2, SULT2A1, GSTM1, GSTP1,
GSTT1, COMT, DPD, MTHFR [Hickman, D. and E. Sim (1991).
"N-acetyltransferase polymorphism. Comparison of phenotype and
genotype in humans" Biochem Pharmacol 42(5): 1007-1014.; Yates, C.
R., E. Y. Krynetski, et al. (1997). "Molecular diagnosis of
thiopurine S-methyltransferase deficiency: genetic basis for
azathioprine and mercaptopurine intolerance." Ann Intern Med
126(8): 608-614.; Bernard, O., J. Tojcic, et al. (2006). "Influence
of nonsynonymous polymorphisms of UGT1A8 and UGT2B7 metabolizing
enzymes on the formation of phenolic and acyl glucuronides of
mycophenolic acid." Drug Metab Dispos 34(9): 1539-1545.; Bushey, R.
T., G. Chen, et al. (2011). "Characterization of
UDP-glucuronosyltransferase 2A1 (UGT2A1) variants and their
potential role in tobacco carcinogenesis." Pharmacogenet Genomics
21(2): 55-65.; Carlini, L. E., N. J. Meropol, et al. (2005).
"UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in
colorectal cancer patients treated with capecitabine/irinotecan."
Clin Cancer Res 11(3): 1226-1236.; Chen, G., A. S. Blevins-Primeau,
et al. (2007). "Glucuronidation of nicotine and cotinine by
UGT2B10: loss of function by the UGT2B10 Codon 67 (Asp>Tyr)
polymorphism." Cancer Res 67(19): 9024-9029.; Chen, G., R. W.
Dellinger, et al. (2008). "Identification of a prevalent functional
missense polymorphism in the UGT2B10 gene and its association with
UGT2B10 inactivation against tobacco-specific nitrosamines."
Pharmacogenet Genomics 18(3): 181-191.; Chen, Y., S. Chen, et al.
(2006). "Genetic variants of human UGT1A3: functional
characterization and frequency distribution in a Chinese Han
population." Drug Metab Dispos 34(9): 1462-1467.; Dellinger, R. W.,
J. L. Fang, et al. (2006). "Importance of
UDP-glucuronosyltransferase 1A10 (UGT1A10) in the detoxification of
polycyclic aromatic hydrocarbons: decreased glucuronidative
activity of the UGT1A10139Lys isoform." Drug Metab Dispos 34(6):
943-949.; Guo, Y., C. Hu, et al. (2012). "Effects of UGT1A6,
UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic
acid in Chinese children with epilepsy." Drug Metab Pharmacokinet.;
He, X., L. M. Hesse, et al. (2009). "Evidence for oxazepam as an in
vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15
D85Y polymorphism but unaffected by UGT2B17 deletion." Br J Clin
Pharmacol 68(5): 721-730.; Park, W. B., P. G. Choe, et al. (2010).
"Genetic factors influencing severe atazanavir-associated
hyperbilirubinemia in a population with low
UDP-glucuronosyltransferase 1A1*28 allele frequency." Clin Infect
Dis 51(1): 101-106.; Parmar, S., J. C. Stingl, et al. (2011).
"Impact of UGT2B7 His268Tyr polymorphism on the outcome of adjuvant
epirubicin treatment in breast cancer." Breast Cancer Res 13(3):
R57.; Saeki, M., Y. Saito, et al. (2004). "Single nucleotide
polymorphisms and haplotype frequencies of UGT2B4 and UGT2B7 in a
Japanese population." Drug Metab Dispos 32(9): 1048-1054.; Sneitz,
N., M. H. Court, et al. (2009). "Human UDP-glucuronosyltransferase
UGT2A2: cDNA construction, expression, and functional
characterization in comparison with UGT2A1 and UGT2A3."
Pharmacogenet Genomics.; Sun, D., G. Chen, et al. (2006).
"Characterization of tamoxifen and 4-hydroxytamoxifen
glucuronidation by human UGT1A4 variants." Breast Cancer Res 8(4):
R50.; Swanson, C., D. Mellstrom, et al. (2007). "The uridine
diphosphate glucuronosyltransferase 2B15 D85Y and 2B17 deletion
polymorphisms predict the glucuronidation pattern of androgens and
fat mass in men." J Clin Endocrinol Metab 92(12): 4878-4882.; Yang,
J., L. Cai, et al. (2012). "Genetic Variations and Haplotype
Diversity of the UGT1 Gene Cluster in the Chinese Population." PLoS
One 7(4): e33988.; Arslan, S. (2010). "Genetic polymorphisms of
sulfotransferases (SULT1A1 and SULT1A2) in a Turkish population."
Biochem Genet 48(11-12): 987-994.; Hirata, H., Y. Hinoda, et al.
(2008). "CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk
factors for endometrial cancer susceptibility." Cancer 112(9):
1964-1973.; Ji, Y., I. Moon, et al. (2007). "Human hydroxysteroid
sulfotransferase SULT2B1 pharmacogenomics: gene sequence variation
and functional genomics." J Pharmacol Exp Ther 322(2): 529-540.;
Ramsey, T. L., H. Y. Meltzer, et al. (2011). "Evidence for a
SULT4A1 haplotype correlating with baseline psychopathology and
atypical antipsychotic response." Pharmacogenomics 12(4): 471-480.;
Tamaki, Y., T. Arai, et al. (2011). "Association between cancer
risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1,
SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in
Japan." Drug Metab Pharmacokinet 26(5): 516-522.; Thomae, B. A., B.
W. Eckloff, et al. (2002). "Human sulfotransferase SULT2A1
pharmacogenetics: genotype-to-phenotype studies." Pharmacogenomics
J 2(1): 48-56.; Thomae, B. A., O. F. Rifki, et al. (2003). "Human
catecholamine sulfotransferase (SULT1A3) pharmacogenetics:
functional genetic polymorphism." J Neurochem 87(4): 809-819.;
Breton, C. V., H. Vora, et al. (2009). "Variation in the GST mu
locus and tobacco smoke exposure as determinants of childhood lung
function." Am J Respir Crit Care Med 179(7): 601-607.; Chen, Y. L.,
H. S. Tseng, et al. (2010). "Glutathione S-Transferase P1 (GSTP1)
gene polymorphism increases age-related susceptibility to
hepatocellular carcinoma." BMC Med Genet 11: 46.; Coles, B. F., F.
Morel, et al. (2001). "Effect of polymorphism in the human
glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2
expression." Pharmacogenetics 11(8): 663-669.; Moyer, A. M., Z.
Sun, et al. (2010). "Glutathione pathway genetic polymorphisms and
lung cancer survival after platinum-based chemotherapy." Cancer
Epidemiol Biomarkers Prev 19(3): 811-821.; Tetlow, N., M. Coggan,
et al. (2004). "Functional polymorphism of human glutathione
transferase A3: effects on xenobiotic metabolism and steroid
biosynthesis." Pharmacogenetics 14(10): 657-663.; Tran, A., F.
Bournerias, et al. (2008). "Serious haematological toxicity of
cyclophosphamide in relation to CYP2B6, GSTA1 and GSTP1
polymorphisms." Br J Clin Pharmacol 65(2): 279-280.; White, D. L.,
D. Li, et al. (2008). "Genetic variants of glutathione
S-transferase as possible risk factors for hepatocellular
carcinoma: a HuGE systematic review and meta-analysis." Am J
Epidemiol 167(4): 377-389.; Zhao, Y., M. Marotta, et al. (2009).
"Linkage disequilibrium between two high-frequency deletion
polymorphisms: implications for association studies involving the
glutathione-S transferase (GST) genes." PLoS Genet 5(5): e1000472.;
Motika, M. S., J. Zhang, et al. (2009). "Novel variants of the
human flavin-containing monooxygenase 3 (FMO3) gene associated with
trimethylaminuria." Mol Genet Metab 97(2): 128-135.; Voisey, J., C.
D. Swagell, et al. (2011). "A novel SNP in COMT is associated with
alcohol dependence but not opiate or nicotine dependence: a case
control study." Behav Brain Funct 7: 51.; Fisher, M. C. and B. N.
Cronstein (2009). "Metaanalysis of methylenetetrahydrofolate
reductase (MTHFR) polymorphisms affecting methotrexate toxicity." J
Rheumatol 36(3): 539-545.; Zhang, X. P., Z. B. Bai, et al. (2012).
"Polymorphisms of dihydropyrimidine dehydrogenase gene and clinical
outcomes of gastric cancer patients treated with fluorouracil-based
adjuvant chemotherapy in Chinese population." Chin Med J (Engl)
125(5): 741-746.].
[0028] There are also numerous examples of polymorphic transporters
and/or receptors and/or other proteins.
[0029] Examples of polymorphic transporters are: [0030] ABCA1,
ABCA2, ABCA3, ABCA4, ABCA7, ABCA8, ABCA12, ABCA13, ABCB1, ABCB2,
ABCB4, ABCB5, ABCB7, ABCB8, ABCB9, ABCB10, ABCB11, ABCC1, ABCC2,
ABCC3, ABCC4, ABCC5, ABCC6, ABCC8, ABCC9, ABCC10, ABCC11, ABCD1,
ABCD2, ABCD3, ABCD4, ABCe1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5,
ABCG8, OAT1, OAT2, OAT3, OAT4, URAT5, OATP1A2, OATP1B1, OATP1B3,
OATP1C1, OATP1B1, OCT1, OCT2, OCT3, OCTN1, OCTN2, SLC22A16 [0031]
[Akiyama, Y., K. I. Fujita, et al. (2011). "Association of ABCC2
genotype with efficacy of first-line FOLFIRI in Japanese patients
with advanced colorectal cancer." Drug Metab Pharmacokinet.; Fukao,
M., K. Ishida, et al. (2011). "Effect of genetic polymorphisms of
SLC28A1, ABCG2, and ABCC4 on bioavailability of mizoribine in
healthy Japanese males." Drug Metab Pharmacokinet 26(5): 538-543.;
Garcia-Donas, J., E. Esteban, et al. (2011). "Single nucleotide
polymorphism associations with response and toxic effects in
patients with advanced renal-cell carcinoma treated with first-line
sunitinib: a multicentre, observational, prospective study." Lancet
Oncol 12(12): 1143-1150.; Hollingworth, P., D. Harold, et al.
(2011). "Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and
CD2AP are associated with Alzheimer's disease." Nat Genet 43(5):
429-435.; Iida, A., S. Saito, et al. (2002). "Catalog of 605
single-nucleotide polymorphisms (SNPs) among 13 genes encoding
human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8,
ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and
ABCG8." J Hum Genet 47(6): 285-310.; Karadeniz, M., M. Erdogan, et
al. (2011). "Effect Of G2706A and G105 1A polymorphisms of the
ABCA1 gene on the lipid, oxidative stress and homocystein levels in
Turkish patients with polycystic ovary syndrome." Lipids Health Dis
10: 193.; Kelsell, D. P., E. E. Norgett, et al. (2005). "Mutations
in ABCA12 underlie the severe congenital skin disease harlequin
ichthyosis." Am J Hum Genet 76(5): 794-803.; Knight, H. M., B. S.
Pickard, et al. (2009). "A cytogenetic abnormality and rare coding
variants identify ABCA13 as a candidate gene in schizophrenia,
bipolar disorder, and depression." Am J Hum Genet 85(6): 833-846.;
Kwan, P., V. Wong, et al. (2011). "Gene-wide tagging study of the
association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms
and multidrug resistance in epilepsy." Pharmacogenomics 12(3):
319-325.; Liptrott, N. J., S. Pushpakom, et al. (2012).
"Association of ABCC10 polymorphisms with nevirapine plasma
concentrations in the German Competence Network for HIV/AIDS."
Pharmacogenet Genomics 22(1): 10-19.; Maia-Lopes, S., J.
Aguirre-Lamban, et al. (2009). "ABCA4 mutations in Portuguese
Stargardt patients: identification of new mutations and their
phenotypic analysis." Mol Vis 15: 584-591.; Matsukawa, T., M.
Asheuer, et al. (2011). "Identification of novel SNPs of ABCD1,
ABCD2, ABCD3, and ABCD4 genes in patients with X-linked
adrenoleukodystrophy (ALD) based on comprehensive resequencing and
association studies with ALD phenotypes." Neurogenetics 12(1):
41-50.; Minster, R. L., S. T. DeKosky, et al. (2009). "No
association of DAPK1 and ABCA2 SNPs on chromosome 9 with
Alzheimer's disease." Neurobiol Aging 30(11): 1890-1891.; Moitra,
K., M. Scally, et al. (2011). "Molecular evolutionary analysis of
ABCB5: the ancestral gene is a full transporter with potentially
deleterious single nucleotide polymorphisms." PLoS One 6(1):
e16318.; Pietrzak-Nowacka, M., K. Safranow, et al. (2012).
"Association of C49620T ABCC8 polymorphism with anthropometric and
metabolic parameters in patients with autosomal dominant polycystic
kidney disease: a preliminary study." Nefrologia 32(2): 153-159.;
Saito, S., A. Lida, et al. (2002). "Identification of 779 genetic
variations in eight genes encoding members of the ATP-binding
cassette, subfamily C (ABCC/MRP/CFTR." J Hum Genet 47(4): 147-171.;
Saito, S., A. Iida, et al. (2002). "Three hundred twenty-six
genetic variations in genes encoding nine members of ATP-binding
cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population."
J Hum Genet 47(1): 38-50.; Sasaki, T., T. Hirota, et al. (2011).
"Systematic screening of human ABCC3 polymorphisms and their
effects on MRP3 expression and function." Drug Metab Pharmacokinet
26(4): 374-386.; Schulz, V., D. Hendig, et al. (2005). "Analysis of
sequence variations in the ABCC6 gene among patients with abdominal
aortic aneurysm and pseudoxanthoma elasticum." J Vasc Res 42(5):
424-432.; Shulenin, S., L. M. Nogee, et al. (2004). "ABCA3 gene
mutations in newborns with fatal surfactant deficiency." N Engl J
Med 350(13): 1296-1303.; Toyoda, Y. and T. Ishikawa (2010).
"Pharmacogenomics of human ABC transporter ABCC11 (MRP8): potential
risk of breast cancer and chemotherapy failure." Anticancer Agents
Med Chem 10(8): 617-624.; Wasmuth, H. E., A. Glantz, et al. (2007).
"Intrahepatic cholestasis of pregnancy: the severe form is
associated with common variants of the hepatobiliary phospholipid
transporter ABCB4 gene." Gut 56(2): 265-270.; Yin, J. Y., Q. Huang,
et al. (2009). "Characterization and analyses of multidrug
resistance-associated protein 1 (MRP1/ABCC1) polymorphisms in
Chinese population." Pharmacogenet Genomics 19(3): 206-216.; Yu,
X., H. Xie, et al. (2011). "Association of MDR1 gene SNPs and
haplotypes with the tacrolimus dose requirements in Han Chinese
liver transplant recipients." PLoS One 6(11): e25933.; Lee, W., H.
Glaeser, et al. (2005). "Polymorphisms in human organic
anion-transporting polypeptide 1A2 (OATP1A2): implications for
altered drug disposition and central nervous system drug entry." J
Biol Chem 280(10): 9610-9617.; Mougey, E. B., H. Feng, et al.
(2009). "Absorption of montelukast is transporter mediated: a
common variant of OATP2B1 is associated with reduced plasma
concentrations and poor response." Pharmacogenet Genomics 19(2):
129-138.; Trdan Lu 353 In, T., B. Stieger, et al. (2012). "Organic
anion transporting polypeptides OATP1B1 and OATP1B3 and their
genetic variants influence the pharmacokinetics and
pharmacodynamics of raloxifene." J Transl Med 10(1): 76.; van der
Deure, W. M., P. S. Hansen, et al. (2008). "Thyroid hormone
transport and metabolism by organic anion transporter 1C1 and
consequences of genetic variation." Endocrinology 149(10):
5307-5314.; Vormfelde, S. V., M. Schirmer, et al. (2006).
"Torsemide renal clearance and genetic variation in luminal and
basolateral organic anion transporters." Br J Clin Pharmacol 62(3):
323-335.; Xu, G., V. Bhatnagar, et al. (2005). "Analyses of coding
region polymorphisms in apical and basolateral human organic anion
transporter (OAT) genes [OAT1 (NKT), OAT2, OAT3, OAT4, URAT
(RST)]." Kidney Int 68(4): 1491-1499.; Becker, M. L., L. E. Visser,
et al. (2011). "OCT1 polymorphism is associated with response and
survival time in anti-Parkinsonian drug users." Neurogenetics
12(1): 79-82., Lal, S., Z. W. Wong, et al. (2007). "Novel SLC22A16
polymorphisms and influence on doxorubicin pharmacokinetics in
Asian breast cancer patients." Pharmacogenomics 8(6): 567-575.,
Park, T. J., J. H. Kim, et al. (2011). "Possible association of
SLC22A2 polymorphisms with aspirin-intolerant asthma." Int Arch
Allergy Immunol 155(4): 395-402., Sakata, T., N. Anzai, et al.
(2010). "Functional analysis of human organic cation transporter
OCT3 (SLC22A3) polymorphisms." J Pharmacol Sci 113(3): 263-266.,
Tahara, H., S. W. Yee, et al. (2009). "Functional genetic variation
in the basal promoter of the organic cation/carnitine transporters
OCTN1 (SLC22A4) and OCTN2 (SLC22A5)." J Pharmacol Exp Ther 329(1):
262-271.]
[0032] Particular emphasis is given here to: ABCB1
(p-glycoprotein), ABCC1 (MRP1), ABCG2 (BCRP), OATP1B1, OAT3, OCT1,
OCT2, OCT3, SLC22A16.
[0033] In pharmacotherapy, such differences in enzyme activity or
enzyme quantity may have a dramatic influence on the success of
treatment, since they directly influence the pharmacokinetics--and
here in particular the exposure--of the substances which are
substrates for one or more polymorphic enzymes and of the
metabolite(s) formed by the polymorphic enzyme. The same applies to
such differences in protein activity or protein quantity, since
receptors, transporters or other proteins may also directly
influence the pharmacokinetics--and here in particular the
exposure--of the substances which are substrates for one or more
polymorphic proteins. In addition, a direct effect on the
pharmacodynamics may also occur here if these proteins are involved
in the mechanism of action.
[0034] There was therefore the need for improved pharmacotherapy in
the use of active ingredients, the action of which is dependent on
the quantity or the activity of expressed and/or inhibited/induced
protein variants, enzyme variants, receptor variants or transporter
variants, with said pharmacotherapy compensating for the
aforementioned variations.
[0035] The present invention is based on a novel formulation
concept, more particularly in the form of a fixed-dose combination
(FDC), in which pre-known individual differences in the activity of
a relevant protein are taken into consideration in the dosage of
two or more pharmacologically active substances, of which one or
more are metabolites of the other substance, in order to ensure
optimal success of treatment. The novel formulation concept is
based on compensation of the varying exposure to the parent
substance and one or more active metabolites by a specific dosage
of the combination of parent substance and one/more metabolites
that is individually adapted to the genotype or phenotype. The
pharmacokinetic goal is to establish a "bioequivalence"-like
steady-state situation (i.e. following repeated intake), i.e.
conformity of plasma concentration changes of the concerned
substances within predefined limits (for this purpose, it is
possible to use, for example, the criteria common in another
context; see in this regard "Prior Art"), with respect to a
reference population which has to be defined from the specific
context.
[0036] To study the formulation concept according to the invention,
pharmacotherapy with tamoxifen was chosen as an example, without
restricting the concept to said example.
[0037] In the case of a CYP2D6 polymorphism, a population
consisting of extensive metabolizers (EMs) would be an example of a
meaningful reference population, since this phenotype represents
the wild type and is the most widespread in many geographical
regions [Sistonen, J., A. Sajantila, et al. (2007). "CYP2D6
worldwide genetic variation shows high frequency of altered
activity variants and no continental structure." Pharmacogenet
Genomics 17(2): 93-101.]. Using the example of a known cancer
medicament, tamoxifen, the problem of genotype- or
phenotype-dependent exposure of active metabolites shall be
illustrated without being restrictive thereto.
[0038] Tamoxifen is a well known pharmaceutical ingredient used for
treating oestrogen receptor-positive (ER+) breast cancer. The
parent substance is subject to a complex metabolization scheme,
which is shown in FIG. 1. In the human body (among others),
tamoxifen is converted into three active metabolites
(N-desmethyltamoxifen, 4-hydroxytamoxifen, endoxifen). Among the
active metabolites, endoxifen in particular, a secondary metabolite
of tamoxifen, is of importance, since a large percentage of the
formation of endoxifen is catalysed via the polymorphic CYP2D6. As
a result, the endoxifen concentration in the blood of a breast
cancer patient is dependent on the CYP2D6 genotype or phenotype
thereof. In the case of a CYP2D6 PM, there is practically no CYP2D6
activity and the concentration of the active metabolite endoxifen
is consequently very low Nurdter, T. E., W. Schroth, et al. (2011).
"Activity levels of tamoxifen metabolites at the estrogen receptor
and the impact of genetic polymorphisms of phase I and II enzymes
on their concentration levels in plasma." Clin Pharmacol Ther
89(5): 708-717.; Jin, Y., Z. Desta, et al. (2005). "CYP2D6
Genotype, Antidepressant Use, and Tamoxifen Metabolism During
Adjuvant Breast Cancer Treatment." Journal of the National Cancer
Institute 97(1): 30-39.; Gjerde, J., M. Hauglid, et al. (2008).
"Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene
copy number on tamoxifen metabolism." Ann Oncol 19(1): 56-61.;
Borges, S., Z. Desta, et al. (2006). "Quantitative effect of CYP2D6
genotype and inhibitors on tamoxifen metabolism: implication for
optimization of breast cancer treatment." Clin Pharmacol Ther
80(1): 61-74.; Madlensky, L., L. Natarajan, et al. (2011).
"Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast
cancer outcomes." Clin Pharmacol Ther 89(5): 718-725.; Lim, J. S.,
X. A. Chen, et al. (2011). "Impact of CYP2D6, CYP3A5, CYP2C9 and
CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast
cancer patients." Br J Clin Pharmacol 71(5): 737-750.; Lim, H. S.,
H. Ju Lee, et al. (2007). "Clinical implications of CYP2D6
genotypes predictive of tamoxifen pharmacokinetics in metastatic
breast cancer." J Clin Oncol 25(25): 3837-3845.; Kiyotani, K., T.
Mushiroda, et al. (2010). "Significant effect of polymorphisms in
CYP2D6 and ABCC2 on clinical outcomes of adjuvant tamoxifen therapy
for breast cancer patients." J Clin Oncol 28(8): 1287-1293.; Irvin,
W. J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen
Dosing Increases Active Metabolite Exposure in Women With Reduced
CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24):
3232-32391. In the case of a CYP2D6 IM, the endoxifen concentration
is likewise still distinctly below the level which can observed in
the case of an EM or the (relatively rare in Europeans) UM
phenotype. In this connection, a study also showed a distinct gene
dosage effect between CYP2D6 EM, IM, and PM genotypes or phenotypes
and their respective steady-state endoxifen concentrations [Jin,
Y., Z. Desta, et al. (2005). "CYP2D6 Genotype, Antidepressant Use,
and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment."
Journal of the National Cancer Institute 97(1): 30-39]. The
genotype- or phenotype-dependent exposures of endoxifen are shown
by way of example in FIG. 2. Within a population of breast cancer
patients, the exposure of endoxifen is thus dependent on the
frequency distribution of the various CYP2D6 genotypes or
phenotypes. This frequency distribution differs greatly between
regions or ethnic groups [Bernard, S., K. A. Neville, et al.
(2006). "Interethnic differences in genetic polymorphisms of CYP2D6
in the U.S. population: clinical implications." Oncologist 11(2):
126-135.; Bradford, L. D. (2002). "CYP2D6 allele frequency in
European Caucasians, Asians, Africans and their descendants."
Pharmacogenomics 3(2): 229-243.; Sachse, C., J. Brockmoller, et al.
(1997). "Cytochrome P450 2D6 variants in a Caucasian population:
allele frequencies and phenotypic consequences." Am J Hum Genet
60(2): 284-295.; Sistonen, J., A. Sajantila, et al. (2007). "CYP2D6
worldwide genetic variation shows high frequency of altered
activity variants and no continental structure." Pharmacogenet
Genomics 17(2): 93-101.]. In the case of Europeans, EM is the
predominant genotype [Sistonen, J., A. Sajantila, et al. (2007).
"CYP2D6 worldwide genetic variation shows high frequency of altered
activity variants and no continental structure." Pharmacogenet
Genomics 17(2): 93-101.].
[0039] There is now a range of studies which provides evidence for
the dependency of the therapeutic success of tamoxifen on the
CYP2D6 genotype or phenotype Wijl, M., R. van Schaik, et al.
(2009). "The CYP2D6*4 polymorphism affects breast cancer survival
in tamoxifen users." Breast Cancer Res Treat 118(1): 125-130.;
Bonanni, B., D. Macis, et al. (2006). "Polymorphism in the CYP2D6
Tamoxifen-Metabolizing Gene Influences Clinical Effect but Not Hot
Flashes: Data From the Italian Tamoxifen Trial." Journal of
Clinical Oncology 24(22): 3708-3709.; Brauch, H., W. Schroth, et
al. (2008). "Clinical Relevance of CYP2D6 Genetics for Tamoxifen
Response in Breast Cancer." Breast Care (Basel) 3(1): 43-50.;
Brauch, H. B., W. Schroth, et al. (2011). "CYP2D6 and Tamoxifen:
Awaiting the Denouement." Journal of Clinical Oncology 29(34):
4589-4590.; Goetz, M. P., A. Kamal, et al. (2008). "Tamoxifen
pharmacogenomics: the role of CYP2D6 as a predictor of drug
response." Clin Pharmacol Ther 83(1): 160-166.; Goetz, M. P., S. K.
Knox, et al. (2007). "The impact of cytochrome P450 2D6 metabolism
in women receiving adjuvant tamoxifen." Breast Cancer Res Treat
101(1): 113-121.; Goetz, M. P., J. M. Rae, et al. (2005).
"Pharmacogenetics of tamoxifen biotransformation is associated with
clinical outcomes of efficacy and hot flashes." J Clin Oncol
23(36): 9312-9318.; Ingelman-Sundberg, M., S. C. Sim, et al.
(2007). "Influence of cytochrome P450 polymorphisms on drug
therapies: pharmacogenetic, pharmacoepigenetic and clinical
aspects." Pharmacol Ther 116(3): 496-526.; Newman, W. G., K. D.
Hadfield, et al. (2008). "Impaired tamoxifen metabolism reduces
survival in familial breast cancer patients." Clin Cancer Res
14(18): 5913-5918.; Schroth, W., L. Antoniadou, et al. (2007).
"Breast cancer treatment outcome with adjuvant tamoxifen relative
to patient CYP2D6 and CYP2C19 genotypes." J Clin Oncol 25(33):
5187-5193.; Schroth, W., M. P. Goetz, et al. (2009). "Association
between CYP2D6 polymorphisms and outcomes among women with early
stage breast cancer treated with tamoxifen." JAMA 302(13):
1429-1436; Goetz, M. P., et al., CYP2D6 metabolism and patient
outcome in the Austrian Breast and Colorectal Cancer Study Group
trial (ABCSG) 8. Clin Cancer Res, 2013. 19(2): p. 500-7.; Brauch,
H., et al., Tamoxifen Use in Postmenopausal Breast Cancer: CYP2D6
Matters. J Clin Oncol, 20121. According to these studies, PMs
consequently benefit distinctly less from tamoxifen therapy than
IMs, and these in turn less than EMs or UMs, and this is reflected,
for example, in published relapse-free survival curves (so-called
Kaplan-Meier plots). Examples of such published plots are shown in
FIG. 3. In the past, these study results were interpreted to mean
that the main action in breast cancer therapy with tamoxifen
originates from its metabolite endoxifen (tamoxifen is occasionally
also referred to in the literature as a "prodrug" [Goetz, M. P., A.
Kamal, et al. (2008). "Tamoxifen pharmacogenomics: the role of
CYP2D6 as a predictor of drug response." Clin Pharmacol Ther 83(1):
160-166.]). Experts are also currently discussing the proposal of
whether endoxifen should not be directly administered instead of
tamoxifen, and initial studies have been published which have the
goal of authorization of pure endoxifen as an agent for breast
cancer therapy [Ahmad, A., S. M. Ali, et al. (2010). "Orally
administered endoxifen is a new therapeutic agent for breast
cancer." Breast Cancer Res Treat 122(2): 579-584.; Ahmad, A., S.
Shahabuddin, et al. (2010). "Endoxifen, a new cornerstone of breast
cancer therapy: demonstration of safety, tolerability, and systemic
bioavailability in healthy human subjects." Clin Pharmacol Ther
88(6): 814-817.].
Similarly, there have been discussions for some time among experts
[de Graan, A. J., S. F. Teunissen, et al. (2011). "Dextromethorphan
as a phenotyping test to predict endoxifen exposure in patients on
tamoxifen treatment." J Clin Oncol 29(24): 3240-3246.; Irvin, W.
J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen
Dosing Increases Active Metabolite Exposure in Women With Reduced
CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24):
3232-3239.; Brauch, H., W. Schroth, et al. (2008). "Clinical
Relevance of CYP2D6 Genetics for Tamoxifen Response in Breast
Cancer." Breast Care (Basel) 3(1): 43-50.; Lim, J. S., X. A. Chen,
et al. (2011). "Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19
polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer
patients." Br J Clin Pharmacol 71(5): 737-750.] as to whether
patients should not be genotyped or phenotyped prior to tamoxifen
treatment in order to restrict administration to the EMs and UMs,
who benefit more (and so patients with the CYP2D6 PM and IM
genotype or phenotype would have to manage without this inherently
important treatment option). A further therapy strategy which is
currently being discussed is that of increasing the dose of
tamoxifen on the basis of genotype or phenotype in order to
achieve, in patients of the CYP2D6 IM and PM phenotype, similar
endoxifen concentrations as are achieved in CYP2D6 EM patients
under normal tamoxifen therapy. In this connection, one study shows
that this approach might possibly be a solution for CYP2D6 IM
patients, but for patients of the CYP2D6 PM phenotype, comparable
concentrations of endoxifen were definitely not achieved.
Consequently, this option is not conceivable for patients of the
CYP2D6 PM phenotype [Irvin, W. J., Jr., C. M. Walko, et al. (2011).
"Genotype-Guided Tamoxifen Dosing Increases Active Metabolite
Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter
Study." J Clin Oncol 29(24): 3232-3239.].
[0040] According to the latest scientific knowledge, it has to be
assumed that the positive action of tamoxifen in ER+ breast cancer
can be attributed to the combination of the active components.
Without doubt, tamoxifen itself has an anti-oestrogenic (and thus
cancer-inhibiting) action, as do the two primary metabolites
4-hydroxytamoxifen and N-desmethyltamoxifen, which would not
circulate in the plasma of the patient if endoxifen were
administered, and it has to be assumed that the entire action of
tamoxifen therapy is only achieved through the interplay of the
parent substance and its active metabolites [V. C. Craig, Long-Term
Tamoxifen Treatment for Breast Cancer, S. 32, Allen, K. E., E. R.
Clark, et al. (1980). "Evidence for the metabolic activation of
non-steroidal antioestrogens: a study of structure-activity
relationships." Br J Pharmacol 71(1): 83-91.; Kemp, J. V., H. K.
Adam, et al. (1983). "Identification and biological activity of
tamoxifen metabolites in human serum." Biochem Pharmacol 32(13):
2045-2052.]. Consequently, it is doubtful whether exclusive
endoxifen therapy can be a meaningful alternative to tamoxifen
therapy; on the contrary, it has to be assumed that sole endoxifen
administration is not an appropriate measure against the
CYP2D6-dependence of tamoxifen therapy in oestrogen
receptor-positive breast cancer.
[0041] The scientific prior art relating to tamoxifen therapy in
breast cancer is very well documented. Although it concerns a
relatively old substance, the CYP2D6 genotype- or
phenotype-dependence of tamoxifen therapy is the subject of current
research and lively discussions in the specialist field.
[0042] There was therefore the specific need for a tamoxifen
treatment which takes into account the CYP2D6 genotype or phenotype
and which enables patients of the CYP2D6 IM and PM phenotype to
achieve endoxifen concentrations similar to those achieved in
CYP2D6 EM patients under normal tamoxifen therapy and might
accordingly also lead to promising therapy in the PMs and IMs in
the form of breast cancer risk minimization.
[0043] To achieve the object, the present invention proposes
combined administration of tamoxifen and endoxifen in a
pharmaceutical formulation, more particularly in a fixed-dose
combination (FDC). In a preferred embodiment, the formulation
according to the invention, more particularly the FDC, is dosed in
a genotype- or phenotype-specific manner.
[0044] FDCs consisting of two or more substances which are not
related to one another like parent substance and metabolite are
known according to the prior art and are, for example, used
successfully in HIV therapy, type 2 diabetes therapy, hypertension
therapy, hyperlipidaemia therapy or in the therapy of malaria and
tuberculosis [Anvikar, A. R., B. Sharma, et al. (2012).
"Artesunate-amodiaquine fixed dose combination for the treatment of
Plasmodium falciparum malaria in India." Malar J 11(1): 97. Ayede,
I. A., A. G. Falade, et al. (2010). "An open randomized clinical
trial in comparing two artesunate-based combination treatments on
Plasmodium falciparum malaria in Nigerian children:
artesunate/sulphamethoxypyrazine/pyrimethamine (fixed dose over 24
hours) versus artesunate/amodiaquine (fixed dose over 48 hours)."
Malar J 9: 378., Bramlage, P., W. P. Wolf, et al. (2010).
"Effectiveness and tolerability of a fixed-dose combination of
olmesartan and amlodipine in clinical practice." Vasc Health Risk
Manag 6: 803-811., Gadzhanova, S., M. Gillies, et al. (2011).
"Fixed dose combination diabetes medicines--usage in the Australian
veteran population." Aust Fam Physician 40(10): 811-815., Honda,
M., M. Ishisaka, et al. (2011). "Open-label randomized multicenter
selection study of once daily antiretroviral treatment regimen
comparing ritonavir-boosted atazanavir to efavirenz with fixed-dose
abacavir and lamivudine." Intern Med 50(7): 699-705., Kauf, T. L.,
K. L. Davis, et al. (2012). "Spillover adherence effects of
fixed-dose combination HIV therapy." Patient Prefer Adherence 6:
155-164., Kim, S. H., K. H. Ryu, et al. (2011). "Efficacy of
fixed-dose amlodipine and losartan combination compared with
amlodipine monotherapy in stage 2 hypertension: a randomized,
double blind, multicenter study." BMC Res Notes 4: 461., Mathew, J.
L. (2009). "Fixed dose drug combination for treatment of
tuberculosis." Indian Pediatr 46(10): 877-880., Mengden, T., R.
Hubner, et al. (2011). "Office and ambulatory blood pressure
control with a fixed-dose combination of candesartan and
hydrochlorothiazide in previously uncontrolled hypertensive
patients: results of CHILI CU Soon." Vasc Health Risk Manag 7:
761-769., Mengden, T., S. Uen, et al. (2009). "Management of
hypertension with fixed dose combinations of candesartan cilexetil
and hydrochlorothiazide: patient perspectives and clinical
utility." Vasc Health Risk Manag 5: 1043-1058., Okpechi, I. G., H.
S. Schoeman, et al. (2011). "Achieving blood pressure goals sTudy
in uncontrolled hypeRtensive pAtients treated with a fixed-dose
combination of ramipriL/hydrochlorothiazide: the ASTRAL study."
Cardiovasc J Afr 22(2): 79-84., Reynolds, J. K. (2009). "Fixed-dose
combination of sitagliptin and metformin for the treatment of type
2 diabetes." Diabetes Metab Syndr Obes 2: 127-134., Shiga, Y., S.
Miura, et al. (2011). "Comparison of the efficacy and safety of
single-pill fixed-dose combinations of losartan/hydrochlorothiazide
and valsartan/hydrochlorothiazide in patients with hypertension
(SALT-VAT study)." Intern Med 50(21): 2477-2483.].
[0045] The advantages compared to separate administration of two or
more active ingredients are the simpler logistics, the reduced
costs in manufacture and distribution, and (crucial in the case of
tamoxifen/endoxifen) improved compliance in the patients.
[0046] A fixed-dose combination, more particularly a genotype- or
phenotype-specific FDC, containing a parent substance and one or
more potential metabolites and serving to compensate for genotype-
or phenotype-related variability of the metabolite concentration is
not known according to the prior art. Similarly, a fixed-dose
combination containing a parent substance and one or more potential
metabolites and serving to compensate for "phenotype-copying"
related variability of the metabolite concentration is not known
according to the prior art. Here, "phenotype-copying" means that,
as a result of simultaneous administration of one medicament which
is converted into one/more active metabolites via an enzyme and one
potent enzyme inhibitor or enzyme inducer which inhibits or induces
said conversion, the original phenotype of the patient is converted
into another on the basis of the interaction between enzyme and
enzyme inhibitor or enzyme inducer. A plausible example here is the
administration of a potent CYP2D6 inhibitor (for example,
paroxetine) to a patient of the CYP2D6 EM phenotype who is
simultaneously receiving tamoxifen. As a result of the active
ingredient-mediated (for example, paroxetine) CYP2D6 inhibition,
the original CYP2D6 EM patient is in effect an IM or PM and has,
accordingly, lower endoxifen concentrations, the active secondary
metabolite of tamoxifen [Borges, S., Z. Desta, et al. (2006).
"Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen
metabolism: implication for optimization of breast cancer
treatment." Clin Pharmacol Ther 80(1): 61-74.; Jin, Y., Z. Desta,
et al. (2005). "CYP2D6 Genotype, Antidepressant Use, and Tamoxifen
Metabolism During Adjuvant Breast Cancer Treatment." Journal of the
National Cancer Institute 97(1): 30-39., Stearns, V., M. D.
Johnson, et al. (2003). "Active tamoxifen metabolite plasma
concentrations after coadministration of tamoxifen and the
selective serotonin reuptake inhibitor paroxetine." J Natl Cancer
Inst 95(23): 1758-1764.].
[0047] Instead of breast cancer therapy purely with endoxifen, the
approach involving a combined administration according to the
invention of tamoxifen and endoxifen is advantageous in those
patients who are not sufficiently able to form endoxifen (i.e.
CYP2D6 PMs and IMs), owing to the demonstrated efficacy of
tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen. The goal of
such a combined administration should be to compensate for the
genotype- or phenotype-related reduced formation of endoxifen by
administration of an appropriate endoxifen dose and, at the same
time, to adapt the dose of tamoxifen if necessary such that PMs and
IMs achieve steady-state plasma concentrations of tamoxifen,
N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen comparable
to EMs or UMs under sole tamoxifen administration.
[0048] Beyond the aforementioned advantages of the
tamoxifen-endoxifen FDCs for CYP2D6 IMs and PMs, application of the
proposed fixed combination, more particularly 20 mg of tamoxifen
and 3 mg of endoxifen, may also be advantageous under certain
circumstances in CYP2D6 EMs and IMs. For example, in the initial
phase of tamoxifen therapy, the period until attainment of the
desired equilibrium concentration (also termed steady-state
concentration) can be considerably shortened. In the case of the
standard therapeutic dosage of 20 mg of tamoxifen, the steady-state
concentration of endoxifen in an example population consisting of
European patients of the CYP2D6 EM genotype or phenotype is
achieved after about 80 days [Fabian C, Sternson L, El-Serafi M,
Cain L, Hearne E.; Clinical pharmacology of tamoxifen in patients
with breast cancer: correlation with clinical data. Cancer. 1981
Aug. 15; 48(4):876-82.; Jin Y, Desta Z, Stearns V, Ward B, Ho H,
Lee K H, Skaar T, Storniolo A M, Li L, Araba A, Blanchard R, Nguyen
A, Ullmer L, Hayden J, Lemler S, Weinshilboum R M, Rae J M, Hayes D
F, Flockhart D A.; CYP2D6 genotype, antidepressant use, and
tamoxifen metabolism during adjuvant breast cancer treatment. J
Natl Cancer Inst. 2005 Jan. 5; 97(1):30-9.; Fuchs W S, Leary W P,
van der Meer M J, Gay S, Witschital K, von Nieciecki A.;
Pharmacokinetics and bioavailability of tamoxifen in postmenopausal
healthy women. Arzneimittelforschung. 1996 April; 46(4):418-22.].
By contrast, if the tamoxifen therapy is initially carried out with
the proposed fixed combination, it is shown, on the basis of the
PBPK model, that the effective steady-state concentrations of
endoxifen appear distinctly faster, viz. after just 9 days, as
shown in FIGS. 11 and 12.
[0049] The advantages of the fixed tamoxifen-endoxifen combination
that are shown for the start of breast cancer therapy with
tamoxifen can, in addition, also be transferred to the frequently
occurring real-life situation of continuous medicament intake being
interrupted (also referred to as non-compliance). Such
non-compliance is known in tamoxifen patients and well documented.
Poor compliance is associated with a possible poorer response to
tamoxifen therapy [Barron, T. I., et al., Early discontinuation of
tamoxifen: a lesson for oncologists. Cancer, 2007. 109(5): p.
832-9.; Dezentje, V. O., et al., Effect of concomitant CYP2D6
inhibitor use and tamoxifen adherence on breast cancer recurrence
in early-stage breast cancer. J Clin Oncol, 2010. 28(14): p.
2423-9.; Friese, C. R., et al., Adjuvant endocrine therapy
initiation and persistence in a diverse sample of patients with
breast cancer. Breast Cancer Res Treat, 2013.; Hershman, D. L., et
al., Early discontinuation and nonadherence to adjuvant hormonal
therapy in a cohort of 8,769 early-stage breast cancer patients. J
Clin Oncol, 2010. 28(27): p. 4120-8.; McCowan, C., et al., Cohort
study examining tamoxifen adherence and its relationship to
mortality in women with breast cancer. Br J Cancer, 2008. 99(11):
p. 1763-8.; Partridge, A. H., Non-adherence to endocrine therapy
for breast cancer. Ann Oncol, 2006. 17(2): p. 183-4.; Rae, J. M.,
et al., Cytochrome P450 2D6 activity predicts discontinuation of
tamoxifen therapy in breast cancer patients. Pharmacogenomics J,
2009. 9(4): p. 258-64.; Ruddy, K. J. and A. H. Partridge, Adherence
with adjuvant hormonal therapy for breast cancer. Ann Oncol, 2009.
20(3): p. 401-2; Ziller, V., et al., Adherence to adjuvant
endocrine therapy in postmenopausal women with breast cancer. Ann
Oncol, 2009. 20(3): p. 431-6.].
[0050] In the event of a tamoxifen drug holiday, the plasma levels
of tamoxifen and its active metabolites (thus, endoxifen too in
particular) fall below the therapeutically effective threshold.
Similar to the initial tamoxifen therapy, the fixed combination can
likewise be advantageously used here in CYP2D6 EMs and IMs in order
to speed up the renewed attainment of effective concentrations, as
shown by the results of the simulations in FIGS. 15 to 18.
[0051] Therefore, the present invention firstly provides a
pharmaceutical formulation containing a parent substance, the
action of which is dependent on the quantity or the activity of
expressed and/or inhibited/induced protein variants, enzyme
variants, receptor variants or transporter variants, and one or
more potential metabolites of the parent substance. In particular,
the dosage of the formulation according to the invention is defined
in a genotype- or phenotype-specific manner.
[0052] However, such a combined formulation of multiple
pharmaceutically active substances is associated with difficulties.
The main difficulty is that of determining the optimal endoxifen
and tamoxifen dose which ensures the therapeutically effective
steady-state plasma levels in CYP2D6 PMs and IMs.
[0053] In the present invention, this further object was, by way of
example, achieved by means of a method based on the use of a
coupled physiologically based pharmacokinetic (PBPK) model for
tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen and endoxifen.
Said method and the corresponding commercially available model
PK-Sim.RTM./MoBi.RTM. are described in the applications
WO2007/147539, WO05/116854 and WO 05/033982, the teachings of which
are hereby integrated in this respect, and are used in the present
invention to develop a method based on a coupled PBPK model. The
development of the coupled PBPK model for tamoxifen,
N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in CYP2D6
EMs and PMs has already been described [Dickschen, K., et al.,
Physiologically-based pharmacokinetic modeling of tamoxifen and its
metabolites in women of different CYP2D6 phenotypes provides new
insight into the tamoxifen mass balance. Frontiers in Pharmacology,
2012. 3.]. The method was subsequently used, by way of example, to
optimize the tamoxifen and endoxifen doses in CYP2D6 PMs and IMs.
The only difference between the published CYP2D6 PM model
parameterization and the CYP2D6 IM parameterization additionally
presented here is the factor used for CYP2D6 enzyme activity (IM:
0.62; PM 0.015 Koller, J. K., N. Krebsfaenger, et al. (2002). "The
influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation
of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver."
Br J Clin Pharmacol 54(2): 157-167.1). FIG. 4 shows a diagram of
the coupled PBPK model for tamoxifen and its three active
metabolites (N-desmethyltamoxifen, 4-hydroxytamoxifen,
endoxifen).
[0054] Therefore, the present invention further provides a method
for preparing a fixed-dose combination pharmaceutical formulation
comprising a parent substance, the action of which is dependent on
the amount or the activity of expressed and/or inhibited/induced
protein variants, enzyme variants, receptor variants or transporter
variants, and at least one metabolite of the parent substance,
comprising the following steps: [0055] a) inputting of an organism,
of its genotype or phenotype, of the parent substance and at least
the metabolite of the parent substance, of an optimal reference
steady-state plasma level for the parent substance for a reference
genotype or reference phenotype in the case of delivery of the
parent substance alone into an input module, [0056] b) forwarding
of the data from a) into a calculation module comprising a
substance data module, an organism data module, a genotype data
module or a phenotype data module, and a physiologically based
pharmacokinetic model, wherein the substance data module comprises
data concerning the physicochemical and/or biochemical properties
of the substance(s), the organism module comprises data concerning
the compartments of the organism, and the genotype data module or
phenotype data module comprises genotype- or phenotype-specific
data, [0057] c) automatically selecting parent substance and
metabolite-specific data from the substance data module, [0058] d)
automatically selecting organism-specific data from the organism
data module on the basis of input a), [0059] e) automatically
selecting genotype- or phenotype-specific data from the genotype
data module or phenotype data module, [0060] f) forwarding of the
selected data from a) to e) into the physiologically based
pharmacokinetic model, [0061] g) calculating, by means of the
physiologically based pharmacokinetic model, an optimized dosage
for the parent substance for the reference genotype or reference
phenotype in order to attain the inputted optimal reference plasma
level for the parent substance from a), [0062] h) calculating the
reference steady-state plasma level for the metabolites
(N-desmethyltamoxifen, 4-hydroxytamoxifen, endoxifen) for the
reference genotype or reference phenotype in the case of
administration of the dose of parent substance calculated in g),
[0063] i) calculating a plasma level of the metabolite(s) that is
reduced owing to the genotype or phenotype inputted in a) with
respect to the corresponding reference plasma level in the case of
administration of the dose of parent substance calculated in g),
[0064] j) calculating a metabolite dose and a parent substance dose
for the combined attainment of the reference plasma level for the
metabolite(s) from h) and of the reference plasma level for the
parent substance from a), [0065] k) outputting the metabolite dose
and the parent substance dose for the fixed-dose combination
pharmaceutical formulation via an output module, and/or [0066] l)
forwarding the dose calculated in j) into an automated device for
dosing medicaments.
[0067] In the present invention, automated devices for dosing
medicaments mean devices for preparing dosage forms such as, for
example, tablets, capsules, liquid dosage or elements thereof, and
also apparatuses for measuring out the dosage, such as a balance,
unit-dose systems known in the prior art, or a device for
volumetrically or gravimetrically measuring out liquids.
[0068] Optionally, the calculation module additionally has an
administration module which comprises data concerning dosage forms
such as, for example, tablets, capsules, liquid dosage, or elements
thereof. Said data usually comprise release properties of the
dosage form, such as immediate, delayed release and also
differentiated (e.g. by means of a layered active-ingredient
distribution) or simultaneous release (e.g. by means of joint
granulation) for combination formulations. In the input module, the
dosage form can then be selectively defined, and the data
concerning the corresponding dosage form are automatically selected
from the administration module and forwarded to the physiologically
based pharmacokinetic model.
[0069] The calculation module calculates the optimal medicament
dose for the parent substance and the metabolite(s) and, where
appropriate, an optimal dosing regimen. It consists of
computer-implemented software and the hardware required to execute
the program. The hardware is generally a commercially available PC.
It is either directly connected to an input device, as in the case
of a laptop computer with a built-in keyboard or chip card reader,
or set up locally and connected to the input device (server). In
principle, all common transmission technologies, both cable-based
and wireless methods, are suitable and conceivable. Particularly
preferred is wireless transmission of the patient information
inputted via the handheld input module or the chip card reader.
[0070] The software makes it possible to manage all information
relevant to calculating the optimal medicament dosage in one or
more databases. In a preferred embodiment of the method, it is also
possible to carry out the calculation of a patient-specific dose.
This information relevant to calculating the medicament dose is
usually divided into organism-specific, substance-specific,
genotype- or phenotype-specific and preferably
administration-specific data, and preferably stored, automatically
retrievable, in corresponding data modules.
[0071] In a preferred embodiment which is particularly relevant to
personalized medication, physiological (or anthropometric)
information, pathological information, possibly information
relating to additionally administered medicaments, so-called
co-medication, are also likewise stored, automatically retrievable,
in date modules as patient-specific data.
[0072] The substance data include, for example, lipophilicity, free
plasma fraction, blood-plasma ratio, partition coefficients,
permeability, volume of distribution, clearance, nature of the
clearance, clearance proportions, nature of the excretion, dosing
regimen, transporter substrate, pharmacokinetic and/or
pharmacodynamic end-point and adverse effects.
[0073] Relevant medicament information is, more particularly, the
recommended therapeutic dosage (according to information from the
manufacturer), pharmacokinetic and/or pharmacodynamic end-point,
clearance (total clearance as blood or plasma clearance in a
reference population or a reference individual) and nature of the
clearance (hepatic-metabolic, biliary, renal, etc.) and the
proportions of the individual processes with respect to the total
clearance, kinetic parameters of active
transporters/receptors/enzymes if the medicament and/or its
metabolite(s) is substrate for one or more active
transporters/receptors/enzymes, and physicochemical and
pharmacokinetic information such as, for example, lipophilicity,
unbound fraction in plasma, plasma proteins to which the medicament
and/or its metabolite(s) binds, blood-plasma distribution
coefficient, or volume of distribution.
[0074] Empirical knowledge which, for example, can be obtained
through the research of case studies can likewise additionally be
part of the databases with substance information or information
relating to co-medication.
[0075] Analogous to patient-specific information, relevant
physiological or anthropometric and pathophysiological information
is, for example, in each case age, gender, race, weight, height,
body mass index, lean body mass, fat-free body mass, gene
expression data, diseases, allergies, medication, renal function
and hepatic function. Relevant pathophysiological information is,
more particularly, diseases, allergies, renal function and hepatic
function.
[0076] In the case of co-medication, the corresponding
aforementioned information concerning all additional administered
medicaments is part of the database relating to the
co-medication.
[0077] The optimal dosage and, where appropriate, the optimal
dosing regimen are calculated on the basis of the
substance-specific data, organism-specific data and genotype- or
phenotype-specific data possibly combined with the
administration-specific data using a rational mathematical model
for calculating the pharmacokinetic and pharmacodynamic behaviour
of the substances to be administered (parent substance and
metabolite(s)) on the basis of the information present in the
databases. In this connection, rational mathematical models can,
for example, be allometric scaling functions or physiologically
based pharmacokinetic models.
[0078] In a preferred embodiment of the invention, a
physiologically based pharmacokinetic/pharmacodynamic simulation
model is used to calculate the individual dosage. Particularly
preferred is the dynamically generated physiologically based
simulation model described in detail in WO2005/633982.
[0079] A particular advantage when using the physiologically based
simulation model from WO2005/633982 is the possibility of
dynamically simulating simultaneous administration of multiple
medicaments and their interaction. In this connection, dynamically
means that, in the interaction, the kinetics of the two (possibly,
also, more than two) interacting substances can be taken into
consideration. This is advantageous over a static consideration in
which, for example, an enzyme or a transporter is completely or
partly inhibited in a time-independent manner, since the dynamic
simulation allows optimization of the dosing regimen. A possible
result of such optimization of the dosing regimen is, for example,
the maintenance of a maximum interval of, for example, 12 hours
(for a once daily administration) when administering two
interacting substances in order to minimize the mutual
influence.
[0080] Particularly suitable for carrying out the method according
to the invention is the systems biology software suite consisting
of PK-Sim.RTM. and MoBi.RTM. from Bayer Technology Services
GmbH.
[0081] Processes such as protein inhibition or induction are known
to be time-dependent, and so interaction effects based on said
processes are also likewise time-dependent. In specific cases,
these dynamic effects, which take place on a time scale of several
days or weeks, can require the need for adaptation of the dose of a
medicament over the course of therapy. A simple static
consideration or merely the issuing of a warning to the handler in
the case of immediate administration of mutually influencing
medicaments, as are known according to the prior art, does not do
justice to such complex, dynamic effects.
[0082] Exemplarily, the method according to the invention is
capable of simulating the steady-state plasma levels of the four
substances tamoxifen, 4-hydroxytamoxifen, N-desmethyltamoxifen and
endoxifen in breast cancer patients with differing CYP2D6 genotypes
or phenotypes according to the tamoxifen dose. Through an
adaptation of the tamoxifen dose, which may be necessary, and a
simultaneous simulation of administration of increasing endoxifen
dosages, the model makes it possible to address the question of the
optimal dosage of the two active ingredients in CYP2D6 IMs and PMs.
In this specific case, the steady-state plasma levels are the
pharmacologically critical parameter; the precise time course of
the plasma concentration is secondary here. According to the
invention, a suitable combination of substances is usually
determined per genotype or phenotype, which combination compensates
for the difference of said genotype or phenotype compared to the
reference.
[0083] As dosage form, commercially available 20 mg tamoxifen
tablet formulations with a once daily administration were taken as
a basis, with none of the formulations being delayed or retarded on
account of the formulation. Such a dosage form is, for example,
described in the product information for Nolvadex.RTM. 20 mg
film-coated tablets from Astra Zeneca or for
Tamoxifen-Ratiopharm.RTM. 10 mg/20 mg/30 mg tablets from
Ratiopharm, in section 6.1 in both cases.
[0084] In the present example, it was possible to show that a
combination consisting of 20 mg of tamoxifen and 3 mg of endoxifen
in CYP2D6 PMs leads to plasma levels of tamoxifen,
N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen that are
comparable to those in the case of sole administration of 20 mg of
tamoxifen in CYP2D6 EMs. In CYP2D6 IMs, the combination of 20 mg of
tamoxifen and 1 mg of endoxifen was found to be optimal (FIGS.
5-7).
[0085] The present invention therefore further provides: [0086] a
fixed-dose combination formulation comprising 15-25 mg of tamoxifen
and 0.25-5.0 mg of endoxifen. [0087] More particularly: [0088] a
fixed-dose combination formulation for CYP2D6 IM patients
comprising 15-25 mg of tamoxifen and 0.25-2.00 mg of endoxifen,
more particularly 18-22 mg of tamoxifen and 0.5-1.5 mg of
endoxifen, particularly preferably 20 mg of tamoxifen and 1.0 mg of
endoxifen (FIG. 8 A b)) and [0089] a fixed-dose combination
formulation for CYP2D6 PM patients comprising 15-25 mg of tamoxifen
and 1.0-5.0 mg of endoxifen, more particularly 18-22 mg of
tamoxifen and 2.0-4.0 mg of endoxifen, more particularly 20 mg of
tamoxifen and 3.0 mg of endoxifen (FIG. 8 A c)).
[0090] Further components of the formulation according to the
invention are known from the above mentioned prior art. For the
preparation of a formulation according to the invention, use is
made of the formulation from, inter alia, the product information
for Nolvadex.RTM. 20 mg film-coated tablets from Astra Zeneca or
for Tamoxifen-Rationpharm.RTM. 10 mg/20 mg/30 mg tablets from
Ratiopharm and Ahmad, A., et al., Endoxifen, a new cornerstone of
breast cancer therapy: demonstration of safety, tolerability, and
systemic bioavailability in healthy human subjects. Clin Pharmacol
Ther, 2010. 88(6): p. 814-7 bzw. US 2009-0291134 A1.
[0091] In order to achieve higher endoxifen exposures in breast
cancer patients, the tamoxifen dose was, in the past, also
increased on an experimental basis. Instead of the 20 mg of
tamoxifen per day, which is effective in CYP2D6 EM, up to 40 mg of
tamoxifen per day as two individual doses were administered in
CYP2D6 IMs and PMs. However, even this severe increase in the dose
of the parent substance did not lead to the endoxifen
concentrations observed in CYP2D6 EMs following a therapeutic dose
of 20 mg of tamoxifen [Irvin, W. J., Jr., et al., Genotype-Guided
Tamoxifen Dosing Increases Active Metabolite Exposure in Women With
Reduced CYP2D6 Metabolism: A Multicenter Study. J Clin Oncol, 2011.
29(24): p. 3232-9.]. Therefore, a particular advantage of the
described genotype- or phenotype-specific combined administration
of tamoxifen and endoxifen is that the tamoxifen exposure in CYP2D6
IMs and PMs is not greatly elevated compared to the CP2D6 EMs (in
contrast to the increase in tamoxifen dose that is currently being
propagated in the scientific community).
[0092] However, since tamoxifen (and similarly the propagated
non-fixed-dose combination therapy of tamoxifen and endoxifen in
CYP2D6 PMs and IMs) must be taken once daily over a long period
(typically 5 years), a second difficulty of a potential combination
therapy is that of ensuring best possible compliance. It is known
that compliance (and thus the success of treatment) in the case of
a medicamentous therapy drops with the number of tablets which must
be taken. For this reason, it is advantageous to combine tamoxifen
and endoxifen to form an FDC. An FDC then contains in each case a
defined dose of the two active ingredients, dependent on the CYP2D6
genotype or phenotype (PM or IM), in the form of a single dosage
form (e.g. tablet or capsule).
[0093] Thus, a further preferred embodiment of the invention is in
each case a genotype- or phenotype-specific fixed-dose combination
of tamoxifen and endoxifen in the aforementioned ratios.
[0094] The approach shown using the example of tamoxifen/endoxifen
can also be readily transferred to other combinations of parent
substance plus one (or more) metabolites, the formation of which is
influenced by genotypic or phenotypic particularities and by the
phenomenon of "phenotype copying", which has already been mentioned
above. More particularly, for the optimization of codeine action,
an 1-DC, more precisely a genotype- or phenotype-specific FDC of
codeine and morphine (the conversion of which from codeine is
likewise catalysed by CYP2D6), would be applicable.
[0095] Examples of further potential candidates would be, inter
alia: ezlopitant, donepezil, clopidogrel, cyclophosphamide,
azathioprine, irinotecan, leflunomide, capecitabine, prasugrel,
venlafaxine, losartan, tolterodine, tramadol, oxycodone,
hydrocodone, doxorubicin, mycophenolate mofetil, estramustine,
ifosfamide, gemcitabine, etoposide, terfenadine, methotrexate.
[0096] The described invention of a pharmaceutical formulation,
preferably an FDC, containing a parent substance and one or more
metabolites can be readily transferred to other active-ingredient
candidates. In the tamoxifen-endoxifen example detailed above, the
problem is the insufficient conversion of tamoxifen to endoxifen in
patients having a CYP2D6 IM or PM phenotype. As shown exemplarily,
the combination of the standard dose of the parent substance with a
genotype- or phenotype-specific endoxifen dose for CYP2D6 IMs or
for CYP2D6 PMs in a fixed combined pharmaceutical formulation can
make up for this insufficiency and differences in the therapy
response are eliminated.
[0097] Essentially, the principle of a genotype- or
phenotype-specific pharmaceutical formulation, preferably an 1-DC,
consisting of a parent substance and one or more metabolites can be
firstly transferred to all parent substances which, owing to a
polymorphic enzyme, protein, receptor or transporter, are converted
into one or more active metabolites and/or bound and/or transported
and/or develop their pharmacodynamic action.
[0098] A further example of the conversion of a parent substance
into an active metabolite via a polymorphic enzyme is clopidogrel.
Clopidogrel inhibits blood coagulation, after it has been converted
into its active metabolite, by blocking ADP-dependent thrombocyte
activation via the glycoprotein IIb/IIIa receptor complex.
Clopidogrel is converted into its active metabolite via, inter
alia, the polymorphic enzyme CYP2C19. CYP2C19 is subject to a
pronounced genetic polymorphism. Similar to CYP2D6, CYP2C19 PMs can
therefore be found in the population. Here, too, it is reasonable
to suspect that patients having a CYP2C19 P M genotype or phenotype
might not benefit sufficiently from therapy with clopidogrel [Simon
T, Bhatt D L, Bergougnan L, Farenc C, Pearson K, Perrin L, Vicaut
E, Lacreta F, Hurbin F, Dubar M.; Genetic polymorphisms and the
impact of a higher clopidogrel dose regimen on active metabolite
exposure and antiplatelet response in healthy subjects., Clin
Pharmacol Ther. 2011 August; 90(2):287-95.; Lee J B, Lee K A, Lee K
Y.; Cytochrome P450 2C19 polymorphism is associated with reduced
clopidogrel response in cerebrovascular disease. Yonsei Med J. 2011
September; 52(5):734-8.; Kazui M, Nishiya Y, Ishizuka T, Hagihara
K, Farid N A, Okazaki O, Ikeda T, Kurihara A.; Identification of
the human cytochrome P450 enzymes involved in the two oxidative
steps in the bioactivation of clopidogrel to its pharmacologically
active metabolite. Drug Metab Dispos. 2010 January; 38(1):92-9.;
Savi P, Pereillo J M, Uzabiaga M F, Combalbert J, Picard C,
Maffrand J P, Pascal M, Herbert J M.; Identification and biological
activity of the active metabolite of clopidogrel. Thromb Haemost.
2000 November, 84(5):891-6.; Cervinski M A, Schwab M C, Lefferts J
A, Lewis L D, Lebel K A, Tyropolis A M, Pflueger S M, Tsongalis G
J.; Establishment of a CYP2C19 genotyping assay for clinical use.
Am J Clin Pathol. 2013 February, 139(2):202-7; Frelinger A L 3rd,
Lee R D, Mulford D J, Wu J, Nudurupati S, Nigam A, Brooks J K,
Bhatt D L, Michelson A D.; A randomized, 2-period, crossover design
study to assess the effects of dexlansoprazole, lansoprazole,
esomeprazole, and omeprazole on the steady-state pharmacokinetics
and pharmacodynamics of clopidogrel in healthy volunteers. J Am
Coll Cardiol. 2012 Apr. 3, 59(14):1304-11.; Gong I Y, Crown N, Suen
C M, Schwarz U I, Dresser G K, Knauer M J, Sugiyama D, Degorter M
K, Woolsey S, Tirona R G, Kim R B.; Clarifying the importance of
CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and
in vivo antiplatelet response. Eur Heart J. 2012 November,
33(22):2856-2464a.; Mega J L, Hochholzer W, Frelinger A L 3rd, Kluk
M J, Angiolillo D J, Kereiakes D J, Isserman S, Rogers W J, Ruff C
T, Contant C, Pencina M J, Scirica B M, Longtine J A, Michelson A
D, Sabatine M S.; Dosing clopidogrel based on CYP2C19 genotype and
the effect on platelet reactivity in patients with stable
cardiovascular disease. JAMA. 2011 Nov. 23, 306(20):2221-8.;
Zabalza M, Subirana I, Sala J, Lluis-Ganella C, Lucas G, Tomas M,
Masia R, Marrugat J, Brugada R, Elosua R.; Meta-analyses of the
association between cytochrome CYP2C19 loss- and gain-of-function
polymorphisms and cardiovascular outcomes in patients with coronary
artery disease treated with clopidogrel. Heart. 2012 January;
98(2):100-8., Yamamoto K, Hokimoto S, Chitose T, Morita K, Ono T,
Kaikita K, Tsujita K, Abe T, Deguchi M, Miyagawa H, Saruwatari J,
Sumida H, Sugiyama S, Nakagawa K, Ogawa H., Impact of CYP2C19
polymorphism on residual platelet reactivity in patients with
coronary heart disease during antiplatelet therapy. J Cardiol. 2011
March; 57(2):194-201.; Jin B, Ni H C, Shen W, Li J, Shi H M, Li Y.;
Cytochrome P450 2C19 polymorphism is associated with poor clinical
outcomes in coronary artery disease patients treated with
clopidogrel. Mol Biol Rep. 2011 March; 38(3):1697-702., Shuldiner A
R, O'Connell J R, Bliden K P, Gandhi A, Ryan K, Horenstein R B,
Damcott C M, Pakyz R, Tantry U S, Gibson Q, Pollin T I, Post W,
Parsa A, Mitchell B D, Faraday N, Herzog W, Gurbel P A.;
Association of cytochrome P450 2C19 genotype with the antiplatelet
effect and clinical efficacy of clopidogrel therapy. JAMA. 2009
Aug. 26, 302(8):849-57.; Sibbing D, Stegherr J, Latz W, Koch W,
Mehilli J, Donler K, Morath T, Schomig A, Kastrati A, von Beckerath
N.; Cytochrome P450 2C19 loss-of-function polymorphism and stent
thrombosis following percutaneous coronary intervention. Eur Heart
J. 2009 April, 30(8):916-22.; Hulot J S, Bura A, Villard E, Azizi
M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P.;
Cytochrome P450 2C19 loss-of-function polymorphism is a major
determinant of clopidogrel responsiveness in healthy subjects.
Blood. 2006 Oct. 1, 108(7):2244-71. Using the concept according to
the invention, it is possible too in this case to calculate a
genotype- or phenotype-specific pharmaceutical formulation,
preferably an FDC, consisting of clopidogrel and its active
metabolite in order to make up for the insufficient formation of
active metabolite in CYP2C19 PMs.
[0099] To determine the optimal reference steady-state plasma
level, it is possible to use either determined data, or a
pharmacokinetic model such as PK-Sim.RTM. and MoBi.RTM. which can
calculate the plasma level after input of a reference dose.
[0100] Furthermore, the principle of a genotype- or
phenotype-specific pharmaceutical formulation, preferably an FDC,
consisting of a parent substance and one or more metabolites can be
transferred to all parent substances which, by means of an enzyme,
protein, receptor or transporter which can be inhibited/induced,
are converted into one or more active metabolites and/or bound
and/or transported and/or develop their pharmacodynamic action.
[0101] As already detailed above using the example of tamoxifen and
the CYP2D6 inhibitor paroxetine, the required simultaneous
administration of a pharmaceutical ingredient A and a
pharmaceutical ingredient B, where A must be converted into an
active metabolite via an enzyme in order to develop its entire
action and B inhibits said enzyme, can in effect convert a patient
from an EM genotype or phenotype into a PM genotype or phenotype.
As a result of the medically indicated simultaneous administration
of paroxetine, the patient is in effect converted into a CYP2D6 PM,
which can, accordingly, convert less tamoxifen into endoxifen.
Using the concept detailed above, it is likewise possible here to
calculate a genotype- or phenotype-specific pharmaceutical
formulation, preferably an FDC, consisting of tamoxifen and
endoxifen which can make up for the insufficiency of endoxifen
formation from tamoxifen owing to the inhibition of CYP2D6 caused
by paroxetine.
[0102] Analogously, the concept according to the invention is
applicable in the case of a required and medically indicated
simultaneous administration of clopidogrel and the competitive
CYP2C19 inhibitor omeprazole. A resulting reduced conversion of
clopidogrel into its active metabolite can likewise be made up for,
using the concept and method detailed above, by calculating a
genotype- or phenotype-specific pharmaceutical formulation,
preferably an FDC, consisting of clopidogrel and its active
metabolite.
[0103] The concept explained above is also capable of compensating
for a combination of a genetic polymorphism and an enzyme
inhibition and/or enzyme induction which additively reduce/increase
the same or different enzymes or proteins or receptors or
transporters in terms of their activity. This is explained
exemplarily using the example of a patient having a CYP2D6 PM
genotype or phenotype who is receiving tamoxifen therapy and
additionally requires the administration of paroxetine. The effect
on the formation of endoxifen from tamoxifen via CYP2D6 can be
taken into account by the principle detailed above and an optimal
genotype- or phenotype-specific pharmaceutical formulation,
preferably an FDC, consisting of tamoxifen and endoxifen can be
calculated. Analogously, this can also be comprehended using the
example of a patient having a CYP2C19 PM genotype or phenotype
under clopidogrel therapy who now requires the administration of
omeprazole.
FIGURES
[0104] The figures illustrate the inventive concept for tamoxifen
therapy and show the results of the tamoxifen/endoxifen FDC dose
finding using PK-Sim.RTM. as per the method according to the
invention as an example, without restricting the concept to said
example.
[0105] FIG. 1 shows an extract from the complex biotransformation
scheme for tamoxifen in humans. About 90% of tamoxifen is
metabolized to N-desmethyltamoxifen and about 7% to
4-hydroxytamoxifen. Endoxifen is formed from N-desmethyltamoxifen
exclusively via the polymorphic cytochrome P450 (CYP) 2D6. The
formation of 4-hydroxytamoxifen from tamoxifen occurs via the
polymorphic CYP2D6 to an extent of about 50%. Thus, CYP2D6 is
largely involved in the essential endoxifen formation steps
[Coller, J. K., N. Krebsfaenger, et al. (2002). "The influence of
CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent
antioestrogen Z-4-hydroxy-tamoxifen in human liver." Br J Clin
Pharmacol 54(2): 157-167.; Desta, Z., B. A. Ward, et al. (2004).
"Comprehensive evaluation of tamoxifen sequential biotransformation
by the human cytochrome P450 system in vitro: prominent roles for
CYP3A and CYP2D6." J Pharmacol Exp Ther 310(3): 1062-1075.; Kaku,
T., K. Ogura, et al. (2004). "Quaternary ammonium-linked
glucuronidation of tamoxifen by human liver microsomes and
UDP-glucuronosyltransferase 1A4." Biochem Pharmacol 67(11):
2093-2102.; Murdter. T. E., W. Schroth, et al. (2011). "Activity
levels of tamoxifen metabolites at the estrogen receptor and the
impact of genetic polymorphisms of phase I and II enzymes on their
concentration levels in plasma." Clin Pharmacol Ther 89(5):
708-717.; Nishiyama, T., K. Ogura. et al. (2002). "Reverse
geometrical selectivity in glucuronidation and sulfation of cis-
and trans-4-hydroxytamoxifens by human liver
UDP-glucuronosyltransferases and sulfotransferases." Biochem
Pharmacol 63(10): 1817-1830.; Sun, D., G. Chen, et al. (2006).
"Characterization of tamoxifen and 4-hydroxytamoxifen
glucuronidation by human UGT1A4 variants." Breast Cancer Res 8(4):
R50.; Sun, D., A. K. Sharma, et al. (2007). "Glucuronidation of
active tamoxifen metabolites by the human UDP
glucuronosyltransferases." Drug Metab Dispos 35(11):
2006-2014.]
[0106] FIGS. 2A through 2C show cytochrome P450 (CYP) 2D6 genotype-
or phenotype-dependent steady-state concentrations of endoxifen in
the context of tamoxifen therapy in patients of the CYP2D6
extensive metabolizer (EM), intermediate metabolizer (IM) or poor
metabolizer (PM) phenotype. A gene dosage effect of the endoxifen
concentration is evident: patients having two functional CYP2D6
alleles (EMs) show a distinctly higher endoxifen exposure than
patients having only one CYP2D6 functional allele (IMs) or no
functional CYP2D6 allele (PM). FIG. 2A: Kiyotani, K., T. Mushiroda,
et al. (2010). "Significant effect of polymorphisms in CYP2D6 and
ABCC2 on clinical outcomes of adjuvant tamoxifen therapy for breast
cancer patients." J Clin Oncol 28(8): 1287-1293.; Murdter, T. E.,
W. Schroth, et al. (2011). "Activity levels of tamoxifen
metabolites at the estrogen receptor and the impact of genetic
polymorphisms of phase I and II enzymes on their concentration
levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; FIG. 2B:
Lim, J. S., X. A. Chen, et al. (2011). "Impact of CYP2D6, CYP3A5,
CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in
Asian breast cancer patients." Br J Clin Pharmacol 71(5): 737-750.;
Lim, H. S., H. Ju Lee, et al. (2007). "Clinical implications of
CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in
metastatic breast cancer." J Clin Oncol 25(25): 3837-3845.; FIG.
2C: Borges, S., Z. Desta, et al. (2006). "Quantitative effect of
CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication
for optimization of breast cancer treatment." Clin Pharmacol Ther
80(1): 61-74.; Jin, Y., Z. Desta, et al. (2005). "CYP2D6 Genotype,
Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast
Cancer Treatment." Journal of the National Cancer Institute 97(1):
30-39.]
[0107] FIGS. 3A and 3B show relapse-free survival curves
(Kaplan-Meier) for breast cancer patients under tamoxifen therapy
according to the cytochrome P450 (CYP) 2D6 extensive metabolizer
(EM), intermediate metabolizer (IM). or poor metabolizer (PM)
genotype or phenotype. FIG. 3A: Time to (breast cancer) recurrence
(left) and event-free survival/relapse-free survival (right). FIG.
3B: Disease-free survival (left) and overall survival (right).
[Figures from (group 1 to 3): Schroth, W., M. P. Goetz, et al.
(2009). "Association between CYP2D6 polymorphisms and outcomes
among women with early stage breast cancer treated with tamoxifen."
JAMA 302(13): 1429-1436.; Goetz, M. P., S. K. Knox, et al. (2007).
"The impact of cytochrome P450 2D6 metabolism in women receiving
adjuvant tamoxifen." Breast Cancer Res Treat 101(1): 113-121.;
Goetz, M. P., J. M. Rae, et al. (2005). "Pharmacogenetics of
tamoxifen biotransformation is associated with clinical outcomes of
efficacy and hot flashes." J Clin Oncol 23(36): 9312-9318.]
[0108] FIGS. 4A and 4B show a diagram of the compartments of the
coupled physiologically based pharmacokinetic (PBPK) model as used
in PK-Sim.RTM. for the simulation of the cytochrome P450 (CYP) 2D6
genotype- or phenotype-specific formation of N-desmethyltamoxifen,
4-hydroxytamoxifen and endoxifen following the administration of
the parent substance tamoxifen or for the simulation of the
simultaneous administration of tamoxifen and endoxifen according to
the CYP2D6 genotype or phenotype and the resulting serum
concentrations. In the intracellular compartment of the liver,
tamoxifen gives rise to N-desmethyltamoxifen and
4-hydroxytamoxifen, and so the tamoxifen PBPK model acts as a
developing function for the two primary metabolites. Analogously,
the secondary metabolite endoxifen arises in the intracellular
compartments of the PBPK models of N-desmethyltamoxifen and
4-hydroxytamoxifen.
[0109] FIG. 5A shows coupled PBPK models for tamoxifen (TAM),
N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OH), endoxifen
(END) in CYP2D6 extensive metabolizer, intermediate metabolizer and
poor metabolizer (EM/IM/PM) genotype or phenotype populations.
Steady-state plasma concentrations of tamoxifen,
N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen following
once daily administration of 20 mg of tamoxifen over 1 year in
example populations of European women of the cytochrome P450 (CYP)
2D6 extensive metabolizer (EM), intermediate metabolizer (IM) and
poor metabolizer (PM) genotype or phenotype. Box-and-whisker plots
show the 5th, 25th, 50th, 75th, and 95th percentiles of the
respective populations. Symbols represent experimental data for the
model validation [from left to right: Gjerde, J. Geisler, et al.
(2010). "Associations between tamoxifen, estrogens, and FSH serum
levels during steady state tamoxifen treatment of postmenopausal
women with breast cancer." BMC Cancer 10: 313.; Gjerde, J., M.
Hauglid, et al. (2008). "Effects of CYP2D6 and SULT1A1 genotypes
including SULT1A1 gene copy number on tamoxifen metabolism." Ann
Oncol 19(1): 56-61.; Madlensky, L., L. Natarajan, et al. (2011).
"Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast
cancer outcomes." Clin Pharmacol Ther 89(5): 718-725.; Murdter, T.
E., W. Schroth, et al. (2011). "Activity levels of tamoxifen
metabolites at the estrogen receptor and the impact of genetic
polymorphisms of phase I and II enzymes on their concentration
levels in plasma." Clin Pharmacol Ther 89(5): 708-717.; Irvin, W.
J., Jr., C. M. Walko, et al. (2011). "Genotype-Guided Tamoxifen
Dosing Increases Active Metabolite Exposure in Women With Reduced
CYP2D6 Metabolism: A Multicenter Study." J Clin Oncol 29(24):
3232-3239.]. FIG. 5B shows an alternative depiction.
[0110] FIG. 6A shows the result of the endoxifen dose finding using
PK-Sim.RTM. as per the method according to the invention for the
simultaneous administration with tamoxifen in CYP2D6 IM patients.
FIG. 6A shows steady-state plasma concentrations of tamoxifen
(TAM), N-desmethyltamoxifen (NDM). 4-hydroxytamoxifen (4OH) and
endoxifen (END) following once daily administration of 20 mg of
tamoxifen on a daily basis over 1 year in example populations of
European patients with the cytochrome P450 (CYP) 2D6 extensive
metabolizer (EM) or intermediate metabolizer (IM) genotype or
phenotype in comparison with experimental data from patients of the
CYP2D6 EM genotype or phenotype. Steady-state plasma concentrations
of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and
endoxifen in example populations of European patients of the CYP2D6
IM genotype or phenotype following simultaneous once daily
administration of 20 mg of tamoxifen plus 0.5 mg or 1 mg or 1.5 mg
of endoxifen, in addition, over 1 year. CYP2D6 IM patients who
received 20 mg of tamoxifen plus 1 mg of endoxifen showed
equivalent endoxifen concentrations with respect to CYP2D6 EM
patients who received 20 mg of tamoxifen once daily over 1 year.
[From left to right: Gjerde, J. Geisler, et al. (2010).
"Associations between tamoxifen, estrogens, and FSH serum levels
during steady state tamoxifen treatment of postmenopausal women
with breast cancer." BMC Cancer 10: 313.; Gjerde, J., M. Hauglid,
et al. (2008). "Effects of CYP2D6 and SULT1A1 genotypes including
SULT1A1 gene copy number on tamoxifen metabolism." Ann Oncol 19(1):
56-61.; Madlensky, L., L. Natarajan, et al. (2011). "Tamoxifen
metabolite concentrations, CYP2D6 genotype, and breast cancer
outcomes." Clin Pharmacol Ther 89(5): 718-725.; Murdter, T. E., W.
Schroth, et al. (2011). "Activity levels of tamoxifen metabolites
at the estrogen receptor and the impact of genetic polymorphisms of
phase I and II enzymes on their concentration levels in plasma."
Clin Pharmacol Ther 89(5): 708-717.; Irvin. W. J., Jr., C. M.
Walko, et al. (2011). "Genotype-Guided Tamoxifen Dosing Increases
Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism:
A Multicenter Study." J Clin Oncol 29(24): 3232-3239] FIG. 6B shows
an alternative depiction. Serving as comparison are the determined
steady-state trough plasma concentrations of tamoxifen (TAM),
N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OH) and endoxifen
(END) in European patients of the CYP2D6 EM genotype or phenotype
following once daily administration of 20 mg of tamoxifen over 1
year, shown as a grey band (5th-95th percentiles) with a median
(dark-grey line). CYP2D6 IM patients who received 20 mg of
tamoxifen plus 1 mg of endoxifen showed equivalent endoxifen
concentrations with respect to CYP2D6 EM patients who received 20
mg of tamoxifen once daily over 1 year.
[0111] FIG. 7A shows the result of the endoxifen dose finding using
PK-Sim.RTM. as per the method according to the invention for the
simultaneous once daily administration with tamoxifen in CYP2D6 PM
patients. FIG. 7A shows steady-state plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) following administration of 20 mg of
tamoxifen once daily over 1 year in example populations of European
patients with the cytochrome P450 (CYP) 2D6 extensive metabolizer
(EM) or poor metabolizer (PM) genotype or phenotype in comparison
with experimental data from patients of the CYP2D6 EM genotype or
phenotype. Steady-state plasma concentrations of tamoxifen,
N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in example
populations of European patients of the CYP2D6 PM genotype or
phenotype following simultaneous administration of 20 mg of
tamoxifen plus 1 mg or 2 mg or 3 mg or 4 mg of endoxifen, in
addition, over 1 year. CYP2D6 PM patients who received 20 mg of
tamoxifen plus 3 mg of endoxifen showed equivalent endoxifen
concentrations with respect to CYP2D6 EM patients who received 20
mg of tamoxifen once daily over 1 year. [From left to right:
Gjerde, J. Geisler, et al. (2010). "Associations between tamoxifen,
estrogens, and FSH serum levels during steady state tamoxifen
treatment of postmenopausal women with breast cancer." BMC Cancer
10: 313.; Gjerde, J., M. Hauglid, et al. (2008). "Effects of CYP2D6
and SULT1A1 genotypes including SULT1A1 gene copy number on
tamoxifen metabolism." Ann Oncol 19(1): 56-61.; Madlensky, L., L.
Natarajan, et al. (2011). "Tamoxifen metabolite concentrations,
CYP2D6 genotype, and breast cancer outcomes." Clin Pharmacol Ther
89(5): 718-725.; Murdter, T. E., W. Schroth, et al. (2011).
"Activity levels of tamoxifen metabolites at the estrogen receptor
and the impact of genetic polymorphisms of phase I and II enzymes
on their concentration levels in plasma." Clin Pharmacol Ther
89(5): 708-717.; Irvin, W. J., Jr., C. M. Walko, et al. (2011).
"Genotype-Guided Tamoxifen Dosing Increases Active Metabolite
Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter
Study." J Clin Oncol 29(24): 3232-3239.1 FIG. 7B shows an
alternative depiction. Serving as comparison are the pre-determined
steady-state trough plasma concentrations of tamoxifen (TAM),
N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OH) and endoxifen
(END) in European patients of the CYP2D6 EM genotype or phenotype
following once daily administration of 20 mg of tamoxifen over 1
year, shown as a grey band (5th-95th percentiles) with a median
(dark-grey line). CYP2D6 PM patients who received 20 mg of
tamoxifen plus 3 mg of endoxifen showed equivalent endoxifen
concentrations with respect to CYP2D6 EM patients who received 20
mg of tamoxifen once daily over 1 year.
[0112] FIG. 8 shows genotype- or phenotype-based dosing of
tamoxifen and endoxifen as a loose combination (A) or as an FDC
(B).
[0113] FIGS. 9 and 10 show a diagram of the modular design of
PK-Sim.RTM..
[0114] FIGS. 11 to 14 show the influence of an initial breast
cancer therapy with the fixed combination of 20 mg of tamoxifen and
3 mg of endoxifen on the attainment of the endoxifen steady-state
concentrations, systematically investigated by means of the PBPK
model for CYP2D6 EMs and IMs.
[0115] FIG. 11 shows the result of the loading dose study using
PK-Sim.RTM. as per the method according to the invention for the
simultaneous administration of tamoxifen and endoxifen in CYP2D6 EM
patients. FIG. 11 shows the trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) following simultaneous once daily
administration of 20 mg of tamoxifen and 3 mg of endoxifen in
European patients having the cytochrome P450 (CYP) 2D6 extensive
metabolizer (EM) genotype or phenotype. Serving as comparison are
the pre-determined steady-state trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) in European patients of the CYP2D6 EM
genotype or phenotype following once daily administration of 20 mg
of tamoxifen over 1 year, shown as a grey band (5th-95th
percentiles) with a median (dark-grey line). Taken as the time
point was the day before the day on which the median trough level
of the endoxifen concentration first exceeds the median
trough-level endoxifen concentration in the example population
consisting of European patients of the CYP2D6 EM genotype or
phenotype under standard therapy, in this case, day 9.
[0116] FIG. 12 shows the result of the loading-dose control study
using PK-Sim.RTM. as per the method according to the invention for
the simultaneous administration of tamoxifen and endoxifen in
CYP2D6 EM patients. FIG. 12 shows the trough plasma concentrations
of tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) following simultaneous once daily
administration of 20 mg of tamoxifen in European patients having
the cytochrome P450 (CYP) 2D6 extensive metabolizer (EM) genotype
or phenotype. Serving as comparison are the pre-determined
steady-state trough plasma concentrations of tamoxifen (TAM),
N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OH) and endoxifen
(END) in European patients of the CYP2D6 EM genotype or phenotype
following once daily administration of 20 mg of tamoxifen over 1
year, shown as a grey band (5th-95th percentiles) with a median
(dark-grey line). Taken as the time point was the day on which the
median trough level of the endoxifen concentration first reaches
the median trough-level endoxifen concentration in the example
population consisting of European patients of the CYP2D6 EM
genotype or phenotype under standard therapy, in this case, day
120.
[0117] FIG. 13 shows the result of the loading dose study using
PK-Sim.RTM. as per the method according to the invention for the
simultaneous administration of tamoxifen and endoxifen in CYP2D6 IM
patients. FIG. 13 shows the trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) following simultaneous once daily
administration of 20 mg of tamoxifen and 3 mg of endoxifen in
European patients having the cytochrome P450 (CYP) 2D6 intermediate
metabolizer (IM) genotype or phenotype. Serving as comparison are
the pre-determined steady-state trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) in European patients of the CYP2D6 EM
genotype or phenotype following once daily administration of 20 mg
of tamoxifen over 1 year, shown as a grey band (5th-95th
percentiles) with a median (dark-grey line). Taken as the time
point was the day before the day on which the median trough level
of the endoxifen concentration first exceeds the median
trough-level endoxifen concentration in the example population
consisting of European patients of the CYP2D6 EM genotype or
phenotype under standard therapy, in this case, day 13.
[0118] FIG. 14 shows the result of the loading-dose control study
using PK-Sim.RTM. as per the method according to the invention for
the simultaneous administration of tamoxifen and endoxifen in
CYP2D6 IM patients. FIG. 14 shows the trough plasma concentrations
of tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) following simultaneous once daily
administration of 20 mg of tamoxifen and 1 mg of endoxifen in
European patients having the cytochrome P450 (CYP) 2D6 intermediate
metabolizer (IM) genotype or phenotype. Serving as comparison are
the pre-determined steady-state trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) in European patients of the CYP2D6 EM
genotype or phenotype following once daily administration of 20 mg
of tamoxifen over 1 year, shown as a grey band (5th-95th
percentiles) with a median (dark-grey line). Taken as the time
point was the day on which the median trough level of the endoxifen
concentration first reaches the median trough-level endoxifen
concentration in the example population consisting of European
patients of the CYP2D6 EM genotype or phenotype under standard
therapy, in this case, day 67.
[0119] In summary, the direct comparison between the administration
of 20 mg of tamoxifen in CYP2D6 EMs or 20 mg of tamoxifen and 1 mg
of endoxifen according to the invention in IMs and the
administration according to the invention of 20 mg of tamoxifen and
3 mg of endoxifen in CYP2D6 EMs or IMs clearly shows that the
endoxifen steady-state concentration is reached substantially
faster with the administration of the FDC (consisting of 20 mg of
tamoxifen and 3 mg of endoxifen), on average about 111 days or 54
days faster, than with the standard dose (consisting of 20 mg of
tamoxifen for EMs and 20 mg of tamoxifen and 1 mg of endoxifen
according to the invention).
[0120] FIGS. 15 to 18 show simulations in the investigation of
non-compliance. The following scenarios were simulated:
[0121] FIG. 15 shows the result of the compliance-dose study using
PK-Sim.RTM. as per the method according to the invention for the
simultaneous administration of tamoxifen and endoxifen in CYP2D6 EM
patients. FIG. 15 shows the trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM). 4-hydroxytamoxifen
(4OH) and endoxifen (END) following administration of 20 mg of
tamoxifen once daily for 6 months and drug holidays of 2, 4, 8 and
12 weeks in duration in European patients having the cytochrome
P450 (CYP) 2D6 extensive metabolizer (EM) genotype or phenotype.
This was subsequently followed by the simultaneous once daily
administration of 20 mg of tamoxifen and 3 mg of endoxifen. Serving
as comparison are the pre-determined steady-state trough plasma
concentrations of tamoxifen (TAM), N-desmethyltamoxifen (NDM),
4-hydroxytamoxifen (4OH) and endoxifen (END) in European patients
of the CYP2D6 EM genotype or phenotype following once daily
administration of 20 mg of tamoxifen over 1 year, shown as a grey
band (5th-95th percentiles) with a median (dark-grey line). Taken
as the time point was the day before the day on which the median
trough level of the endoxifen concentration first exceeds the
median trough-level endoxifen concentration in the example
population consisting of European patients of the CYP2D6 EM
genotype or phenotype under standard therapy, in this case, day 2
after the start of FDC intake in the case of the 2-week drug
holiday, day 3 after the start of FDC intake in the case of the
4-week drug holiday, day 7 after the start of FDC intake in the
case of the 8-week drug holiday, and day 9 after the start of FDC
intake in the case of the 12-week drug holiday.
[0122] FIG. 16 shows the result of the compliance-dose control
study using PK-Sim.RTM. as per the method according to the
invention for the simultaneous administration of tamoxifen and
endoxifen in CYP2D6 EM patients. FIG. 16 shows the trough plasma
concentrations of tamoxifen (TAM), N-desmethyltamoxifen (NDM),
4-hydroxytamoxifen (4OH) and endoxifen (END) following
administration of 20 mg of tamoxifen once daily for 6 months and
drug holidays of 2, 4, 8 and 12 weeks in duration in European
patients having the cytochrome P450 (CYP) 2D6 extensive metabolizer
(EM) genotype or phenotype. This was subsequently followed by the
once daily administration of 20 mg of tamoxifen. Serving as
comparison are the pre-determined steady-state trough plasma
concentrations of tamoxifen (TAM). N-desmethyltamoxifen (NDM),
4-hydroxytamoxifen (4OH) and endoxifen (END) in European patients
of the CYP2D6 EM genotype or phenotype following once daily
administration of 20 mg of tamoxifen over 1 year, shown as a grey
band (5th-95th percentiles) with a median (dark-grey line). Taken
as the time point was the day on which the median trough level of
the endoxifen concentration first reaches the median trough-level
endoxifen concentration in the example population consisting of
European patients of the CYP2D6 EM genotype or phenotype under
standard therapy, in this case, day 269 after the start of FDC
intake in the case of the 2-week drug holiday, day 334 after the
start of FDC intake in the case of the 4-week drug holiday, day
>336 after the start of FDC intake in the case of the 8-week
drug holiday, and day >336 after the start of FDC intake in the
case of the 12-week drug holiday.
[0123] FIG. 17 shows the result of the compliance-dose study using
PK-Sim.RTM. as per the method according to the invention for the
simultaneous administration of tamoxifen and endoxifen in CYP2D6 IM
patients. FIG. 17 shows the trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) following simultaneous administration of
20 mg of tamoxifen and 1 mg of endoxifen once daily for 6 months
and drug holidays of 2, 4, 8 and 12 weeks in duration in European
patients having the cytochrome P450 (CYP) 2D6 intermediate
metabolizer (IM) genotype or phenotype. This was subsequently
followed by the simultaneous once daily administration of 20 mg of
tamoxifen and 3 mg of endoxifen. Serving as comparison are the
pre-determined steady-state trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) in European patients of the CYP2D6 EM
genotype or phenotype following once daily administration of 20 mg
of tamoxifen over 1 year, shown as a grey band (5th-95th
percentiles) with a median (dark-grey line). Taken as the time
point was the day before the day on which the median trough level
of the endoxifen concentration first exceeds the median
trough-level endoxifen concentration in the example population
consisting of European patients of the CYP2D6 EM genotype or
phenotype under standard therapy, in this case, day 4 after the
start of FDC intake in the case of the 2-week drug holiday, day 7
after the start of FDC intake in the case of the 4-week drug
holiday, day 10 after the start of FDC intake in the case of the
8-week drug holiday, and day 11 after the start of FDC intake in
the case of the 12-week drug holiday.
[0124] FIG. 18 shows the result of the compliance-dose control
study using PK-Sim.RTM. as per the method according to the
invention for the simultaneous administration of tamoxifen and
endoxifen in CYP2D6 IM patients. FIG. 18 shows the trough plasma
concentrations of tamoxifen (TAM), N-desmethyltamoxifen (NDM).
4-hydroxytamoxifen (4OH) and endoxifen (END) following simultaneous
administration of 20 mg of tamoxifen and 1 mg of endoxifen once
daily for 6 months and drug holidays of 2, 4, 8 and 12 weeks in
duration in European patients having the cytochrome P450 (CYP) 2D6
intermediate metabolizer (IM) genotype or phenotype. This was
subsequently followed by the once daily simultaneous administration
of 20 mg of tamoxifen and 1 mg of endoxifen. Serving as comparison
are the pre-determined steady-state trough plasma concentrations of
tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen
(4OH) and endoxifen (END) in European patients of the CYP2D6 EM
genotype or phenotype following once daily administration of 20 mg
of tamoxifen over 1 year, shown as a grey band (5th-95th
percentiles) with a median (dark-grey line). Taken as the time
point was the day on which the median trough level of the endoxifen
concentration first reaches the median trough-level endoxifen
concentration in the example population consisting of European
patients of the CYP2D6 EM genotype or phenotype under standard
therapy, in this case, day 217 after the start of FDC intake in the
case of the 2-week drug holiday, day 250 after the start of FDC
intake in the case of the 4-week drug holiday, day 283 after the
start of FDC intake in the case of the 8-week drug holiday, and day
315 after the start of FDC intake in the case of the 12-week drug
holiday.
[0125] In summary, the simulation results from FIGS. 15 to 18 show
that the fixed combined administration of 20 mg of tamoxifen and 3
mg of endoxifen is advantageous for speeding up the attainment of
the effective steady-state concentrations of endoxifen in the event
of non-compliance.
* * * * *
References