About DEPOTREX^®

Naltrexone has been available for many years in an oral dose form as a treatment for narcotic addiction and it has also been found to be useful in treating alcohol addiction. The oral dose form has some drawbacks: the daily dose is rather high (50 mg) and the patient can easily discontinue medication and return to narcotic usage. There is poor compliance and a very high dropout rate.

Ongoing clinical studies with Depotrex^®, biot27's depot naltrexone microcapsules, illustrate how controlled delivery can be of tremendous value in treatment of addictions and alcoholism. With the Depotrex^® formulation, monthly injections greatly aid in treatment compliance, and the required dose is substantially less than that given orally.

Depotrex^® is prepared from injectable biodegradable microcapsules using biot27's proprietary Microcoat^TM microencapsulation process. Work with Depotrex^® has been sponsored for the past several years by the National Institute on Drug Abuse (NIDA) and the National Institute on Alcohol Abuse and Alcoholism (NIAAA). The microcapsules shown were prepared for the treatment of opioid addiction and alcohol dependency.

Pharmacokinetics and Pharmacodynamics of Depotrex^® in Rhesus Monkeys

An 8-week study on 9 Rhesus monkeys was carried out. Depotrex^® was injected IM at one dose level and SC at two dose levels. Blood levels of naltrexone were monitored, and periodic morphine challenges were administered to evaluate the blockage of narcotic behavioral effects. Naltrexone plasma levels persisted over the effective 2 ng/ml level for 25-33 days, depending on the dosages and injection site. Depotrex^® caused complete blockage of the stereotypical morphine symptoms through 17 days, with almost complete or partial blockage evident at 31 days.

Human Clinical Studies

Study of Depotrex^® in Healthy Volunteers - A study in healthy subjects was conducted by Stephen J. Heishman, M.D. (Heishman, et al., 1993). Eight volunteers were used. Two individuals received subcutaneous injections containing 52 mg of naltrexone, two received placebo, and four received doses containing 103 mg naltrexone. Results indicated no tissue irritation or infection at the injection sites, and no adverse physical signs and symptoms. Psychomotor (digit-symbol substitution) and cognitive (digit recall) performance was not affected. Hematology and chemistry laboratory results were normal.

Studies of Depotrex^® in Drug Addicts - BIOTEK's Depotrex^® naltrexone microcapsules and placebo microcapsules were tested by the National Institute on Drug Abuse. Two studies were conducted.

In the first study (Alim, et al, 1994) a total of 8 subjects received Depotrex^® at doses corresponding from 52 to 206 mg naltrexone and four subjects received an equal amount of biot27's placebo microcapsules. The purpose of the study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of the depot formulation. Eight cocaine dependent males with no evidence of opiate dependence and in good physical health were subjects in the study. Three subjects received a low dose Depotrex^® formulation s.c., two received placebo, and three received a regular Depotrex^® formulation. The regular dose group received an opiate agonist challenge (morphine 10 mg i.v.) on the day before the injection and on days 8, 15, 22, and 29 after Depotrex^® injection. In both groups, subjects reported mild pain during the first few days of post-injection. Even though there was individual variability with the presence of erythema and induration, no subjects required removal of the medication. Mean opiate antagonistic effects appeared to increase up to day 22 in the regular dose group. These preliminary results suggested that the regular dose may be an effective blocking dose for street opiates and that additional investigation of depot naltrexone may be warranted.

The second study (Comer, et al., 2000; Comer, et al., 2002) was designed to evaluate the time course, safety, and effectiveness of Depotrex^®. Twelve heroin-dependent individuals participated in an 8-week inpatient study. After a 1-week detoxification period, participants received two subcutaneous injections: half of the participants received one placebo and one Depotrex^® injection and half of the participants received two Depotrex^® injections. The effects of intravenous heroin (0, 6.25, 12.5, 18.75, 25 mg, i.v.) were evaluated for the next 6 weeks. One dose of heroin was tested per day on Mondays through Fridays, and the entire dose range was tested each week. Heroin doses were administered in ascending order, with the exception that the placebo dose could occur on any day. During each experimental session, subjective, performance, and physiological effects were measured both before and after heroin administration. During the last week of the study, participants were counseled about various treatment options. Results: The low dose of Depotrex^® antagonized heroin-induced ratings of "I Feel High" and "I Feel a Good Drug Effect" for up to 3 weeks; the high dose of Depotrex^® antagonized these subjective ratings for up to 5 weeks. Ratings of "I Want Heroin" were consistently elevated across study weeks and were unaffected by Depotrex^®. Plasma levels of naltrexone remained above 1 ng/mL for approximately 3 and 4 weeks after administration of the lower and higher doses of Depotrex^®, respectively. Other than the initial discomfort associated with the injection of Depotrex^®, there were no untoward side effects.

Studies of Depotrex^® in Alcoholics - A placebo-controlled study of the safety and tolerability of Depotrex^® was conducted in 20 alcohol-dependent subjects. The study was conducted by Dr. Henry Kranzler at the University of Connecticut Health Center (Kranzler, et al., 1998).

All subjects took naltrexone 50 mg orally (p.o.) daily for 2 weeks (to identify those for whom adverse effects contraindicated receiving Depotrex^®), followed by a 2-week, no-medication washout period (which made it possible to collect bioavailability data). Fifteen subjects (75%) then received a single subcutaneous injection of Depotrex^® and five received a placebo injection. All subjects also received weekly relapse prevention psychotherapy. A total of 10 plasma samples were collected during the 8 weeks following injection to permit measurement of naltrexone and 6-b-naltrexol concentrations. Compliance with study visits was high, with 99% of visits having been completed within 3 days of the scheduled date of sample collection. Following the injection, naltrexone plasma concentrations exceeded a mean of 1 ng/mL for 21 days. Plasma concentrations of 6-b-naltrexol were consistently higher and lasted longer than those of the parent compound. Since plasma concentrations and clinical effects were evident for longer than 28 days, 4-week intervals of injection appear suitable for treatment of alcohol dependence.

As hypothesized, subjects receiving Depotrex^® had a significantly lower percentage of heavy drinking days than did placebo-treated subjects. Further individuals treated with the Depotrex^® drank heavily on significantly fewer days during follow-up. Finally, there was a nonsignificant trend for subjects receiving Depotrex^® to have a lower mean number of drinks/day during the injection period. During the follow-up period, the advantage for Depotrex^® over placebo reached statistical significance. Overall, 3 of 5 placebo subjects (60%) and 5 of 15 Depotrex^® subjects (33%) relapsed to heavy drinking following the injection.

1. Alim, T.N., Tai, B., Chiang, N., Lindquist, T., Deutsch, S.I., "Tolerability Study of a Depot Form of Naltrexone in Substance Abusers". Presented at the Annual Meeting of the College on Problems of Drug Dependence, Palm Beach, Florida, June (1994).
2. Comer, S., Collins, E.D., Nuwayser, E.S., Kleber, H.D., and Fischman, M.W., "Depot Naltrexone: Effects on Response to IV Heroin in Humans". Presented at the Annual Meeting of the College on Problems of Drug Dependence, San Juan, Puerto Rico, June (2000).
3. Comer, S.D., Collins, E.D., Kleber, HJ.D., Nuwayser, E.S., Kerrigan, J.H., Fischman, M.W., "Depot naltrexone: long-lasting antagonism of hte effects of heroin in humans". Psychopharmacology 159:351-360 (2002).
4. Heishman, S.J., Francis-Wood, A., Keenan, R.M., Chiang, C.N., Terrill, J.B., Tai, B., and Henningfield, J.E. "Safety and Pharmacokinetics of a New Formulation of Depot Naltrexone". Presented at the Annual Meeting of the College on Problems of Drug Dependence (1993).
5. Kranzler, H. R., Modesto-Lowe, V., and Nuwayser, E. S. (1998) Sustained-release naltrexone for alcoholism treatment: a preliminary study. Alcohol Clin Exp Res, 22(5), 1074-1079.