U.S. patent application number 14/214157 was filed with the patent office on 2014-09-25 for methods for non-toxic treatment for drug withdrawal.
This patent application is currently assigned to DEMERX, INC.. The applicant listed for this patent is Lawrence Friedhoff. Invention is credited to Lawrence Friedhoff.
Application Number | 20140288056 14/214157 |
Document ID | / |
Family ID | 51537436 |
Filed Date | 2014-09-25 |
United States Patent
Application |
20140288056 |
Kind Code |
A1 |
Friedhoff; Lawrence |
September 25, 2014 |
METHODS FOR NON-TOXIC TREATMENT FOR DRUG WITHDRAWAL
Abstract
The disclosure provides a method to administer noribogaine to a
human patient having drug addiction in dosages that provide
efficacy without leading to any significant deleterious clinical
signs.
Inventors: |
Friedhoff; Lawrence; (Fort
Lauderdale, FL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Friedhoff; Lawrence |
Fort Lauderdale |
FL |
US |
|
|
Assignee: |
DEMERX, INC.
Fort Lauderdale
FL
|
Family ID: |
51537436 |
Appl. No.: |
14/214157 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61852485 |
Mar 15, 2013 |
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Current U.S.
Class: |
514/214.02 |
Current CPC
Class: |
A61P 25/36 20180101;
A61P 25/32 20180101; A61K 31/485 20130101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/55 20130101;
A61K 31/137 20130101; A61P 25/30 20180101; A61K 31/55 20130101;
A61P 25/00 20180101 |
Class at
Publication: |
514/214.02 |
International
Class: |
A61K 31/55 20060101
A61K031/55 |
Claims
1. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 1980 ng/mg serum and
an average AUC/24 hr of about 1,100 ng/ml.
2. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 1800 ng/mg serum and
an AUC/24 hr of about 1000 ng/ml.
3. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 1620 ng/mg serum and
an AUC/24 hr of about 900 ng/ml.
4. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 1440 ng/mg serum and
an AUC/24 hr of about 800 ng/ml.
5. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 1260 ng/mg serum and
an AUC/24 hr of about 700 ng/ml.
6. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 1400 ng/mg serum and
an AUC/24 hr of from about 600 ng/ml.
7. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 900 ng/mg serum and
an AUC/24 hr of about 500 ng/ml.
8. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 720 ng/mg serum and
an AUC/24 hr of about 400 ng/ml.
9. A method for treating withdrawal symptoms in a patient suffering
from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 540 ng/mg serum and
an AUC/24 hr of about 300 ng/ml.
10. A method for treating withdrawal symptoms in a patient
suffering from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 360 ng/mg serum and
an AUC/24 hr of about 200 ng/ml.
11. A method for treating withdrawal symptoms in a patient
suffering from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine that provides
a C.sub.max of noribogaine of less than about 180 ng/mg serum and
an AUC/24 hr of about 100 ng/ml.
12. A method for treating withdrawal symptoms in a patient
suffering from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine from about 100
mg to about 600 mg at intervals of about 24 hours.
13. The method according to claim 12, wherein the patient is
administered a dosage of noribogaine from about 100 mg to about 500
mg at intervals of about 24 hours.
14. The method according to claim 12, wherein the patient is
administered a dosage of noribogaine from about 100 mg to about 400
mg at intervals of about 24 hours.
15. The method according to claim 12, wherein the patient is
administered a dosage of noribogaine from about 100 mg to about 300
mg at intervals of about 24 hours.
16. The method according to claim 12, wherein the patient is
administered a dosage of noribogaine from about 100 mg to about 200
mg at intervals of about 24 hours.
17. A method for treating withdrawal symptoms in a patient
suffering from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine from about 200
mg to about 600 mg at intervals of about 24 hours.
18. The method according to claim 17, wherein the patient is
administered a dosage of noribogaine from about 200 mg to about 500
mg at intervals of about 24 hours.
19. The method according to claim 17, wherein the patient is
administered a dosage of noribogaine from about 200 mg to about 400
mg at intervals of about 24 hours.
20. The method according to claim 17, wherein the patient is
administered a dosage of noribogaine from about 200 mg to about 300
mg at intervals of about 24 hours.
21. A method for treating withdrawal symptoms in a patient
suffering from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine from about 300
mg to about 600 mg at intervals of about 24 hours.
22. The method according to claim 21, wherein the patient is
administered a dosage of noribogaine from about 300 mg to about 500
mg at intervals of about 24 hours.
23. The method according to claim 21, wherein the patient is
administered a dosage of noribogaine from about 300 mg to about 400
mg at intervals of about 24 hours. In some embodiments each patient
is administered from about 400 mg to about 500 mg at intervals of
about 24 hours.
24. A method for treating withdrawal symptoms in a patient
suffering from withdrawal from addiction to a substance comprising
administering to the patient a dosage of noribogaine from about 500
mg to about 600 mg at intervals of about 24 hours.
Description
BACKGROUND
[0001] The disclosure relates to the treatment of drug withdrawal
symptoms.
[0002] Withdrawal from drug dependence is characterized by dramatic
and traumatic symptoms, including sweating, racing heart,
palpitations, muscle tension, tightness in the chest, difficulty
breathing, tremor, nausea, vomiting, diarrhea, grand mal seizures,
heart attacks, strokes, hallucinations and delirium tremens (DTs).
Numerous treatments have been developed in attempts to ameliorate
such symptoms.
[0003] Ibogaine has been used as a botanical preparation from the
root bark of iboga tabernathe for over 100 years both as a crude
preparation and as semisynthetic ibogaine, which was marketed in
France until about 1970. Observations in the 1970's suggested that
ibogaine in higher doses was useful as a treatment for addiction.
The use of ibogaine as a treatment for addiction was controversial
because higher doses caused hallucinations and, in spite of many
anecdotal reports of striking efficacy, no double-blind,
placebo-controlled trials supported the efficacy of ibogaine as a
treatment for withdrawal or addiction.
[0004] U.S. Pat. No. 6,348,456 discloses highly purified
noribogaine and teaches that it should be provided at dosages from
about 0.01 to about 100 mg per kg body weight per day.
[0005] More recently, scientists at DemeRx, Inc. evaluated the
pharmacokinetics and metabolism of ibogaine and noted that the
psychotomimetic effects correlated with blood levels of ibogaine,
while the anti-addictive effects correlated with blood levels of
noribogaine, the only metabolite of ibogaine found in humans, dogs,
rats and monkeys. These experiments were followed up with animal
studies of noribogaine in various addiction models, which
demonstrated that noribogaine significantly reduced drug-seeking
behavior and had no activity in an evaluation of psychotomimetic
effects in an animal model. DemeRx is now developing noribogaine as
a treatment for the symptoms of drug addiction and has shown to be
effective in animal models of addiction to alcohol, cocaine and
opiate dependence.
[0006] During pre-clinical toxicity studies in various animal
species, it was found that high doses of noribogaine can cause
convulsions and other CNS-related clinical signs, respiratory
arrest and death. Given the signs of efficacy that noribogaine has
shown, there is a need for a method to administer noribogaine in
dosages that provide efficacy without leading to any significant
deleterious clinical signs.
SUMMARY
[0007] The disclosure provides a method to administer noribogaine
to a human patient having drug addiction in dosages that provide
efficacy without leading to any significant deleterious clinical
signs. Such dosages provide maximum serum concentrations
(C.sub.max) of noribogaine of less than about 2000 ng/mL, while
maintaining efficacious average noribogaine serum levels of between
about 100-2000 ng/ml (AUC/T).
[0008] One embodiment of disclosure provides a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 1980 ng/mg serum and an average AUC/24 hr of about
1,100 ng/ml.
[0009] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 1800 ng/mg serum and an AUC/24 hr of about 1000
ng/ml.
[0010] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 1620 ng/mg serum and an AUC/24 hr of about 900
ng/ml.
[0011] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 1440 ng/mg serum and an AUC/24 hr of about 800
ng/ml.
[0012] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 1260 ng/mg serum and an AUC/24 hr of about 700
ng/ml.
[0013] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 1400 ng/mg serum and an AUC/24 hr of from about 600
ng/ml.
[0014] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 900 ng/mg serum and an AUC/24 hr of about 500
ng/ml.
[0015] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 720 ng/mg serum and an AUC/24 hr of about 400
ng/ml.
[0016] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 540 ng/mg serum and an AUC/24 hr of about 300
ng/ml.
[0017] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 360 ng/mg serum and an AUC/24 hr of about 200
ng/ml.
[0018] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine that provides a C.sub.max of noribogaine of
less than about 180 ng/mg serum and an AUC/24 hr of about 100
ng/ml.
[0019] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine from about 100 mg to about 600 mg at
intervals of about 24 hours.
[0020] In some embodiments, the patient is administered a dosage of
noribogaine from about 100 mg to about 500 mg at intervals of about
24 hours. In some embodiments, the patient is administered a dosage
of noribogaine from about 100 mg to about 400 mg at intervals of
about 24 hours. In some embodiments, the patient is administered a
dosage of noribogaine from about 100 mg to about 300 mg at
intervals of about 24 hours. In some embodiments, the patient is
administered a dosage of noribogaine from about 100 mg to about 200
mg at intervals of about 24 hours.
[0021] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine from about 200 mg to about 600 mg at
intervals of about 24 hours.
[0022] In some embodiments, the patient is administered a dosage of
noribogaine from about 200 mg to about 500 mg at intervals of about
24 hours. In some embodiments, the patient is administered a dosage
of noribogaine from about 200 mg to about 400 mg at intervals of
about 24 hours. In some embodiments, the patient is administered a
dosage of noribogaine from about 200 mg to about 300 mg at
intervals of about 24 hours.
[0023] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine from about 300 mg to about 600 mg at
intervals of about 24 hours.
[0024] In some embodiments, the patient is administered a dosage of
noribogaine from about 300 mg to about 500 mg at intervals of about
24 hours. In some embodiments, the patient is administered a dosage
of noribogaine from about 300 mg to about 400 mg at intervals of
about 24 hours. In some embodiments each patient is administered
from about 400 mg to about 500 mg at intervals of about 24
hours.
[0025] Also provided, in one embodiment, is a method for treating
withdrawal symptoms in a patient suffering from withdrawal from
addiction to a substance comprising administering to the patient a
dosage of noribogaine from about 500 mg to about 600 mg at
intervals of about 24 hours.
DETAILED DESCRIPTION
[0026] The disclosure provides a method to administer noribogaine
to a human patient having drug addiction in dosages that provide
efficacy without leading to any significant deleterious clinical
signs. Such dosages provide maximum serum concentrations
(C.sub.max) of noribogaine of less than about 2000 ng/mL, while
maintaining efficacious average noribogaine serum levels of between
about 100-1100 ng/ml (AUC/24 hr).
[0027] The term "noribogaine" as used herein, refers to noribogaine
as well as its pharmaceutically acceptable salts. In some
embodiments, the methods of the present disclosure entail the
administration of a prodrug of noribogaine that provides the
desired maximum serum concentrations and efficacious average
noribogaine serum levels. A prodrug of noribogaine refers to a
compound that metabolizes, in vivo, to noribogaine. In some
embodiment, the prodrug is selected to be readily cleavable either
by a cleavable linking arm or by cleavage of the prodrug entity
that binds to noribogaine such that noribogaine is generated in
vivo. In one preferred embodiment, the prodrug moiety is selected
to facilitate binding to the .mu. and/or .kappa. receptors in the
brain either by facilitating passage across the blood brain barrier
or by targeting brain receptors other than the .mu. and/or .kappa.
receptors. Examples of prodrugs of noribogaine are provided in U.S.
patent application Ser. No. 13/165,626, the content of which is
incorporated here by reference.
[0028] The following ranges are obtained from a single dose of
noribogaine HCl/fasting patient.
[0029] In certain embodiments, the dosages administered provide a
C.sub.max of noribogaine of less than about 1980 ng/mg serum and an
average AUC/24 hr of about 1,100 ng/ml. In certain embodiments, the
dosages administered provide a C.sub.max of noribogaine of less
than about 1800 ng/mg serum and an AUC/24 hr of about 1000 ng/ml.
In certain embodiments, the dosages administered provide a
C.sub.max of noribogaine of less than about 1620 ng/mg serum and an
AUC/24 hr of about 900 ng/ml. In certain embodiments, the dosages
administered provide a C.sub.max of noribogaine of less than about
1440 ng/mg serum and an AUC/24 hr of about 800 ng/ml. In certain
embodiments, the dosages administered provide a C.sub.max of
noribogaine of less than about 1260 ng/mg serum and an AUC/24 hr of
about 700 ng/ml. In certain embodiments, the dosages administered
provide a C.sub.max of noribogaine of less than about 1400 ng/mg
serum and an AUC/24 hr of from about 600 ng/ml. In certain
embodiments, the dosages administered provide a C.sub.max of
noribogaine of less than about 900 ng/mg serum and an AUC/24 hr of
about 500 ng/ml. In certain embodiments, the dosages administered
provide a C.sub.max of noribogaine of less than about 720 ng/mg
serum and an AUC/24 hr of about 400 ng/ml. In certain embodiments,
the dosages administered provide a C.sub.max of noribogaine of less
than about 540 ng/mg serum and an AUC/24 hr of about 300 ng/ml. In
certain embodiments, the dosages administered provide a C.sub.max
of noribogaine of less than about 360 ng/mg serum and an AUC/24 hr
of about 200 ng/ml. In certain embodiments, the dosages
administered provide a C.sub.max of noribogaine of less than about
180 ng/mg serum and an AUC/24 hr of about 100 ng/ml.
[0030] In some embodiments such concentrations are obtained by
administering from about 100 to about 1,100 mg at intervals of
about 24 hours. In some embodiments such concentrations are
obtained by administering from about 200 mg to about 1,100 mg at
intervals of about 24 hours. In some embodiments such
concentrations are obtained by administering from about 300 mg to
about 1,100 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 400 mg
to about 1,100 mg at intervals of about 24 hours. In some
embodiments such concentrations are obtained by administering from
about 500 mg to about 1,100 mg at intervals of about 24 hours. In
some embodiments such concentrations are obtained by administering
from about 600 mg to about 1,100 mg at intervals of about 24 hours.
In some embodiments such concentrations are obtained by
administering from about 700 mg to about 1,100 mg at intervals of
about 24 hours. In some embodiments such concentrations are
obtained by administering from about 800 mg to about 1,100 mg at
intervals of about 24 hours. In some embodiments such
concentrations are obtained by administering from about 900 mg to
about 1,100 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 1,000
mg to about 1,100 mg at intervals of about 24 hours.
[0031] In some embodiments such concentrations are obtained by
administering from about 100 mg to about 1,100 mg at intervals of
about 24 hours. In some embodiments such concentrations are
obtained by administering from about 100 mg to about 1,000 mg at
intervals of about 24 hours. In some embodiments such
concentrations are obtained by administering from about 100 mg to
about 900 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 800 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 700 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 600 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 500 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 400 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 300 mg at intervals of about 24 hours. In some embodiments
such concentrations are obtained by administering from about 100 mg
to about 200 mg at intervals of about 24 hours.
[0032] Particularly preferred embodiments include the following
dose ranges. In some embodiments each patient is administered from
about 100 mg to about 600 mg at intervals of about 24 hours. In
some embodiments each patient is administered from about 100 mg to
about 500 mg at intervals of about 24 hours. In some embodiments
each patient is administered from about 100 mg to about 400 mg at
intervals of about 24 hours. In some embodiments each patient is
administered from about 100 mg to about 300 mg at intervals of
about 24 hours. In some embodiments each patient is administered
from about 100 mg to about 200 mg at intervals of about 24 hours.
In some embodiments each patient is administered from about 200 mg
to about 600 mg at intervals of about 24 hours. In some embodiments
each patient is administered from about 200 mg to about 500 mg at
intervals of about 24 hours. In some embodiments each patient is
administered from about 200 mg to about 400 mg at intervals of
about 24 hours. In some embodiments each patient is administered
from about 200 mg to about 400 mg at intervals of about 24 hours.
In some embodiments each patient is administered from about 200 mg
to about 300 mg at intervals of about 24 hours. In some embodiments
each patient is administered from about 300 mg to about 400 mg at
intervals of about 24 hours. In some embodiments each patient is
administered from about 300 mg to about 500 mg at intervals of
about 24 hours. In some embodiments each patient is administered
from about 300 mg to about 600 mg at intervals of about 24 hours.
In some embodiments each patient is administered from about 400 mg
to about 500 mg at intervals of about 24 hours. In some embodiments
each patient is administered from about 400 mg to about 600 mg at
intervals of about 24 hours. In some embodiments each patient is
administered from about 500 mg to about 600 mg at intervals of
about 24 hours.
[0033] In some embodiments, the patient is administered
periodically, such as once, twice, three time, four times or five
time daily with noribogaine or its prodrug. In some embodiments,
the administration is once daily, or once every second day, once
every third day, three times a week, twice a week, or once a week.
The dosage and frequency of the administration depends on the route
of administration, content of composition, age and body weight of
the patient, condition of the patient, without limitation.
Determination of dosage and frequency suitable for the present
technology can be readily made a qualified clinician.
[0034] These dose ranges are achieved by oral administration of
noribogaine or its prodrug, which may conveniently be provided in
tablet, caplet, liquid or capsule form. In certain embodiments, the
noribogaine is provided as noribogaine HCl, with dosages reported
as the amount of free base noribogaine. In some embodiments, the
noribogaine HCl is provided in hard gelatin capsules containing
only noribogaine HCl with no excipients.
[0035] Without wishing to be bound by theory, it is believed that
noribogaine provides its anti-withdrawal symptom effects by acting
as both an .alpha.3.beta.4 nicotinic receptor and a serotonin
reuptake blocker acting on the 5-HT Transporter.
[0036] The following Examples are intended to further illustrate
certain embodiments of the disclosure and are not intended to limit
its scope.
Example 1
Single Dose Toxicity in Rats
[0037] The objective of this study was to determine the toxicity
and toxicokinetic profile of noribogaine HCl following a single
oral (gavage) administration in the Sprague-Dawley rat. A single
dose of 100, 300 and 800 mg/kg (achieved with doses of 400 mg/kg 3
h +/-30 min apart because of the limitations of maximum dose
formulation concentration). Five male rats/group were used.
Mortality occurred in all male rats in the 800 mg/kg group,
approximately 2-3 h after administration of the second dose of 400
mg/kg. Hypoactivity, vocalization, chewing movements, changes in
respiration/posture, salivation, stimuli sensitivity, tremors,
twitches and penile erection occurred prior to death. Hypoactivity,
vocalization, salivation, stimuli sensitivity, loss of limb
function and lying on the cage floor occurred on the day of
treatment and persisted until Day 2 in 3/5 rats given 300 mg/kg.
The low dose rats treated at 100 mg/kg did not show any treatment
related signs. The NOAEL was determined to be 100 mg/kg.
Example 2
Single Dose Toxicity in Dogs
[0038] In an acute oral toxicity/TK study in dogs, no mortality
occurred at doses of 5 (n=2) or 10 (n=2) mg/kg. Convulsions and
other CNS-related clinical signs, including twitches, salivation,
vocalization, incoordination and hypoactivity, occurred at a dose
of 10 mg/kg, beginning 20 minutes after dosing and persisting until
3 h 40 m post-dose. The 5 mg/kg dose was considered the NOAEL, as
only transient reduction in food consumption in one dog occurred at
that dose.
Example 3
Single Dose Toxicity in Cynomolgus Monkeys
[0039] The objective of the study was to determine the toxicity and
toxicokinetic profile of noribogaine following oral (gavage)
administration to the cynomolgus monkey. The test article was
administered as follows in Table 1:
TABLE-US-00001 TABLE 1 Toxicity and Toxicokinetic Study in
Cynomolgus monkeys Treatment on Study Day Dose Level (mg/kg) Number
of Animals 1 20 2 males 8 40 2 males 15 80 and 160 2 males * = Each
dose was followed by a 7 day washout period. Dosing was staggered
by 45 minutes. ** = One animal was administered 80 mg/kg and the
other animal was administered 160 mg/kg.
[0040] Parameters monitored on the study included: mortality,
clinical signs and body weights. Blood samples were collected for
TK evaluation. No mortality or treatment related clinical signs
were noted for doses up to and including 160 mg/kg. The single dose
maximum tolerated dose (MTD) was determined to be greater than 160
mg/kg based on the parameters monitored during the study.
Example 4
Fourteen Day Repeat Dose Toxicity and Toxicokinetics in Rats
[0041] This study was conducted to evaluate the toxicity profile of
noribogaine-HCl following oral (gavage) administration to the rat
for 14 days following Table 2 below:
TABLE-US-00002 TABLE 2 Toxicity and Toxicokinetic Study in Rats
Dose Con- Toxicology Animals Toxicokinetics Dose Level centration
Main Recovery Animals Group (mg/kg/day) (mg/mL) Male Female Male
Female Male Female Control 0 0 10 10 5 5 3 3 Low Dose 25 5 10 10 --
-- 6 6 Mid Dose 50 10 10 10 -- -- 6 6 High Dose 100 20 10 10 5 5 6
6
[0042] Male and female Sprague-Dawley rats, 10/sex/group, were
administered 0, 25, 50 or 100 mg/kg noribogaine HCl daily by single
oral gavage for 14 days. An additional 5 rats/sex/group in the 0
(control) and 100 mg/kg groups were retained for a 28 day recovery
period during which no drug was administered. Six rats/sex/group (3
rats/sex controls) were similarly dosed and sampled on study days 1
and 14 for analysis of noribogaine-HCl concentrations in the blood.
Rats were observed for mortality, clinical signs, body weight, food
consumption, ophthalmology (pre-dose, during week 2, and at the end
of recovery), hematology, coagulation, clinical chemistry,
urinalysis, gross necropsy, organ weights and histopathology (full
tissue panel, plus immunocytochemistry of 5 sections of the brain
and spinal cord by staining for GFAP and Calbindin). There were no
test article-related effects on mortality (none occurred), clinical
signs, ophthalmoscopy, hematology, coagulation parameters, clinical
chemistry, urinalysis, gross necropsy or histopathology. Food
consumption and body weight were slightly reduced (food
consumption: -4.7% in males and females; body weight: -5.5% in
males and -2.6% in females) in the high dose (100 mg/kg) groups.
Minor increases in liver weight in the mid- and high dose groups
were not correlated with histopathologic changes and are considered
incidental. No treatment-related differences in the brain were seen
in sections stained for GFAP or Calbindin.
[0043] The NOAEL dose in this study was interpreted to be 100
mg/kg, the highest dose tested in the study.
Example 5
Fourteen Day Repeat Dose Toxicity and Toxicokinetics in Dogs
[0044] The objective of this study was to determine the toxicity
profile of noribogaine HCl given following oral (gavage)
administration to dogs for 14 days according to the following Table
3 below:
TABLE-US-00003 TABLE 3 Toxicity and Toxicokinetic Study in Dogs
Dose Con- Toxicology Animals Group Dose Level centration Main
Recovery Designation (mg/kg/day) (mg/mL) Male Female Male Female
Control 0 0 4 4 4 4 Low Dose 0.5 0.1 4 4 -- -- Mid Dose 1.0 0.2 4 4
-- -- High Dose 5.0 1.0 4 4 4 4
[0045] Noribogaine HCl was administered to groups of 4 male and 4
female dogs by single oral gavage daily for 14 days at doses of 0,
0.5, 1.0 and 5.0 mg/kg/day. An additional group of 4 male and 4
female dogs received either the vehicle control or 5.0 mg/kg/day
for 14 days and were held for an additional 28 days after cessation
of dosing to assess recovery from any potential drug-induced
changes. The study was conducted under GLP guidelines and included
comprehensive examinations of clinical signs, body weight, clinical
pathology parameters, ophthalmologic examinations, ECG recordings
and analyses of plasma for bioanalytical measurement of drug levels
at appropriate intervals during the study. At the termination of
the dosing phase and at the termination of the recovery phase, all
dogs were subjected to a complete post-mortem examination including
gross examination of major organs and histologic examination of an
extensive list of tissues. Additional sections of brain were
obtained from cerebrum, cerebellus, brain stem and spinal cord and
examined histologically to evaluate potential effects on brain
histopathology. In addition, these sections were examined with
immunohistochemical stains for GFAP for evidence of gliosis and
Calbindin for a more comprehensive examination of cerebellar
Purkinje cells. No evidence of adverse effect was observed in any
dog from any treatment group during the dosing or recovery phase in
clinical observations, body weights, clinical pathological
parameters, ophthalmologic examinations, ECG recordings, or gross
lesions at necropsy. The results of the plasma drug level
measurements at Day 1 and Day 14 of the study are shown in the
Table below. Noribogaine-HCl maximum plasma concentrations
(C.sub.max) were reached between 0.5 and 0.9 hours post-dosing,
following which plasma concentrations gradually decreased over a
period of up to 24 hours, except in the male dogs and female dogs
of Group 4, for which significant levels of noribogaine were still
detected at 24 h post-dosing on both Days 1 and 14.
[0046] The only target tissue identified in this study was the
lacrimal gland of dogs receiving 5 mg/kg/day. The lacrimal gland
changes were characterized by slight to moderate atrophy and
degeneration of the acinar cells accompanied by slight to moderate
accumulation of brown/yellow pigment and infiltration of
mononuclear cells. There was an associated mononuclear infiltration
in the draining mandibular lymph nodes of affected dogs in this
dose group. Despite the appearance of isolated ocular abnormalities
in several dogs in this high dose group on ophthalmologic
examination, there was no clear association between these ocular
signs and the appearance of the lacrimal gland changes suggesting
that these morphologic changes did not result in sufficient
functional abnormality of the gland to produce physical changes in
exterior structures of the eye. There was no clear evidence of
local irritation associated with drug treatment in these high dose
dogs. No evidence of drug-induced effect was observed in any other
tissue including the extensive sections of brain evaluated with
conventional histopathology or with immunohistochemistry.
Examination of the animals in the recovery group showed clear
evidence of regeneration of this lacrimal gland change. While
slight atrophy was still evident in the acinar cells of the gland
after 28 days off drug, no evidence of continuing and ongoing
degeneration or cellular infiltration was observed. The NOAEL in
this study was 1 mg/kg/day based on the lacrimal gland changes at 5
mg/kg/day. The results are summarized in Tables 4 and 5.
TABLE-US-00004 TABLE 4 Mean plasma toxicokinetic parameters for
noribogaine in male dogs on days 1 and 14 Gr 2 - 0.5 mg/kg Gr 3 -
1.0 mg/kg Gr 4 - 5.0 mg/kg Parameters D 1 D 14 D 1 D 14 D 1 D 14
T.sub.1/2 (h) 1.3 1.3 1.2 1.8 4.7 6.5 T.sub.max (h) 0.7 0.7 0.9 0.8
0.6 0.9 C.sub.max (ng/ml) 28.8 29.4 58.6 67.6 693 716
AUC.sub.0-last 46.6 53.2 102.5 172.3 3515.0 6403.3 (hr*ng/ml)
AUC.sub.0-24 h 59.7 64.5 119.8 210.4 3515.0 6403.3 (hr*ng/ml)
AUC.sub.0-.infin. 67.8 68.2 120.8 195.7 3630.5 6961.4
(hr*ng/ml)
TABLE-US-00005 TABLE 5 Mean plasma toxicokinetic parameters for
noribogaine in female dogs on days 1 and 14 Gr 2 - 0.5 mg/kg Gr 3 -
1.0 mg/kg Gr 4 - 5.0 mg/kg Parameters D 1 D 14 D 1 D 14 D 1 D 14
T.sub.1/2 (h) 1.0 1.1 1.4 1.6 4.3 5.7 T.sub.max (h) 0.5 1.0 0.8 0.5
0.6 0.6 C.sub.max (ng/ml) 25.3 29.8 68.5 74.1 691 683
AUC.sub.0-last 31.5 35.4 148.9 169.0 3367.9 5951.2 (hr*ng/ml)
AUC.sub.0-24 h 40.4 55.0 176.2 203.7 3367.9 5951.2 (hr*ng/ml)
AUC.sub.0-.infin. 44.9 45.7 165.3 197.0 3425.7 6283.2
(hr*ng/ml)
Example 6
Human Pharmacokinetic Studies
[0047] In double blind studies, fasting healthy volunteers (6 per
cohort) were treated once orally with a tablet of noribogaine HCl.
In escalating cohorts, the volunteers received 3 mg, 10 mg, 30 mg
or 60 mg noribogaine. The results are provided below. All
parameters were linear and no clinically relevant adverse effects
were observed in the trial.
[0048] The subject mean serum levels over time of noribogaine free
base from a single dose of 3 mg noribogaine free base under fasting
conditions were plotted. The mean C.sub.max of 5.2 ng/ml was
observed 1.9 hours after administration, while the mean AUC/24 hr
of 3.1 ng/ml was obtained.
[0049] The subject mean serum levels over time of noribogaine free
base from a single dose of 10 mg noribogaine free base under
fasting conditions were plotted. The mean C.sub.max of 14.5 ng/ml
was observed 2.9 hours after administration, while the mean AUC/24
hr of 10.6 ng/ml was obtained.
[0050] The subject mean serum levels over time of noribogaine free
base from a single dose of 30 mg noribogaine free base under
fasting conditions were plotted. The mean C.sub.max of 55.9 ng/ml
was observed between 1.75 hours after administration, while the
mean AUC/24 of 29.2 ng/ml was obtained.
[0051] The subject mean serum levels over time of noribogaine free
base from a single dose of 60 mg noribogaine free base under
fasting conditions were plotted. The mean C.sub.max of 116 ng/ml
was observed between 1.75 hours after administration, while the
mean AUC/24 ng/ml of 61 was obtained.
[0052] The subject mean serum levels over time of noribogaine free
base for all 4 cohorts were plotted. The extrapolated dosage of
noribogaine free base required to provide a C.sub.max ranging from
about 5.2 ng/ml to about 1980 ng/ml and an AUC/24 hr of about 3.1
ng/ml to about 1100 ng/ml was determined.
* * * * *