METHODS FOR NON-TOXIC TREATMENT FOR DRUG WITHDRAWAL

Info

Publication number: 20140288056
Type: Application
Filed: Mar 14, 2014
Publication Date: Sep 25, 2014
Applicant: DEMERX, INC. (Fort Lauderdale, FL)
Inventor: Lawrence Friedhoff (Fort Lauderdale, FL)
Application Number: 14/214,157

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.

Description

Description

BACKGROUND

The disclosure relates to the treatment of drug withdrawal symptoms.

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.

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.

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.

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.

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

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_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).

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_maxof noribogaine of less than about 1980 ng/mg serum and an average AUC/24 hr of about 1,100 ng/ml.

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_maxof noribogaine of less than about 1800 ng/mg serum and an AUC/24 hr of about 1000 ng/ml.

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_maxof noribogaine of less than about 1620 ng/mg serum and an AUC/24 hr of about 900 ng/ml.

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_maxof noribogaine of less than about 1440 ng/mg serum and an AUC/24 hr of about 800 ng/ml.

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_maxof noribogaine of less than about 1260 ng/mg serum and an AUC/24 hr of about 700 ng/ml.

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_maxof noribogaine of less than about 1400 ng/mg serum and an AUC/24 hr of from about 600 ng/ml.

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_maxof noribogaine of less than about 900 ng/mg serum and an AUC/24 hr of about 500 ng/ml.

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_maxof noribogaine of less than about 720 ng/mg serum and an AUC/24 hr of about 400 ng/ml.

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_maxof noribogaine of less than about 540 ng/mg serum and an AUC/24 hr of about 300 ng/ml.

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_maxof noribogaine of less than about 360 ng/mg serum and an AUC/24 hr of about 200 ng/ml.

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_maxof noribogaine of less than about 180 ng/mg serum and an AUC/24 hr of about 100 ng/ml.

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.

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.

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.

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.

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.

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.

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

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_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).

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 μ and/or κ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the μ and/or κ 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.

The following ranges are obtained from a single dose of noribogaine HCl/fasting patient.

In certain embodiments, the dosages administered provide a C_maxof 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_maxof 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_maxof 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_maxof 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_maxof 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_maxof 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_maxof 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_maxof 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_maxof 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_maxof 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_maxof noribogaine of less than about 180 ng/mg serum and an AUC/24 hr of about 100 ng/ml.

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.

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.

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.

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.

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.

Without wishing to be bound by theory, it is believed that noribogaine provides its anti-withdrawal symptom effects by acting as both an α3β4 nicotinic receptor and a serotonin reuptake blocker acting on the 5-HT Transporter.

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

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

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

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 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.

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

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 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

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.

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

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 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

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_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.

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 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_1/2(h) 1.3 1.3 1.2 1.8 4.7 6.5 T_max(h) 0.7 0.7 0.9 0.8 0.6 0.9 C_max(ng/ml) 28.8 29.4 58.6 67.6 693 716 AUC_0-last 46.6 53.2 102.5 172.3 3515.0 6403.3 (hr*ng/ml) AUC_{0-24 h} 59.7 64.5 119.8 210.4 3515.0 6403.3 (hr*ng/ml) AUC_0-∞ 67.8 68.2 120.8 195.7 3630.5 6961.4 (hr*ng/ml)

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_1/2(h) 1.0 1.1 1.4 1.6 4.3 5.7 T_max(h) 0.5 1.0 0.8 0.5 0.6 0.6 C_max(ng/ml) 25.3 29.8 68.5 74.1 691 683 AUC_0-last 31.5 35.4 148.9 169.0 3367.9 5951.2 (hr*ng/ml) AUC_{0-24 h} 40.4 55.0 176.2 203.7 3367.9 5951.2 (hr*ng/ml) AUC_0-∞ 44.9 45.7 165.3 197.0 3425.7 6283.2 (hr*ng/ml)

Example 6 Human Pharmacokinetic Studies

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.

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_maxof 5.2 ng/ml was observed 1.9 hours after administration, while the mean AUC/24 hr of 3.1 ng/ml was obtained.

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_maxof 14.5 ng/ml was observed 2.9 hours after administration, while the mean AUC/24 hr of 10.6 ng/ml was obtained.

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_maxof 55.9 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 of 29.2 ng/ml was obtained.

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_maxof 116 ng/ml was observed between 1.75 hours after administration, while the mean AUC/24 ng/ml of 61 was obtained.

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_maxranging 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.

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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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.