National Institute on Drug Abuse
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`15-HOV-1995 BLDSCBOSTON SPA
`LS23 ?BQ
`NIOA RESEARCH ONOGRAPH
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`·~
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`MONOGRAPH 6110.170000
`Ac~
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`VOL 141
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`PB
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`111
`
`Problems of Drug
`Dependence, 1993:
`Proceedings of the
`55th Annual Scientific
`Meeting
`The College on Problems
`of Drug Dependence, Inc.
`Volume II
`
`LOAN BAN ExPIRES
`
`(~ .. 4- U.S. D•partmenl ttl He•Hh iiAd Human St!rvice• • Public H
`
`llh Senlice • NATIONAL INSTITUTES OF HEALTH
`
`Supplied by the British Library 16 Mar 2018, 09:07 (GMT)
`
`APOTEX EXHIBIT 1014
`Apotex v. Alkermes
`IPR2025-00514
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`

`

`Problems of Drug
`Dependence, 1993:
`Proceedings of the 55th Annual
`Scientific Meeting, The College on
`Problems of Drug Dependence, Inc.
`
`Volume II: Abstracts
`
`Editor:
`
`Louis S. Harris, Ph.D.
`
`NIDA Research Monograph 141
`1994
`
`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`National Institutes of Health
`
`National Institute on Drug Abuse
`5600 Fishers Lane
`Rockville, MD 20857
`
`Supplied by the British Library 16 Mar 2018, 09:07 (GMT)
`
`

`

`l
`
`SAFETY AND PHARMACOKINETICS OF A NEW
`FORMULATION OF DEPOT NALTREXONE
`S. J. Heishman, A. Francis-Wood, R. M, Keenan, C. N. Chiang, J. B.
`Terrill, B. Tal, and J. E. Henningfi.eld
`
`Nallrexone hydrochloride (Trexan) is an opioid anragonist. devoid of agonist activity,
`indicated in the maintenance of 1111 opioid-free stale in detox.iflCd fonnerty opioid-dependent
`individuals. Typically, individuals are dosed with 50-150 mg of oral naluexone every 24-
`72 hours. A maJor constraint on its utility ns n treatment modality has been the lack of
`acceptance by chents, du in pan to the frequency of dosing and incidence of adverse side
`effects.
`
`The development of a depot formulation providing long-term opioid rea:ptor blockade vi
`sustained release of low level of naltrexonc may avoid th
`problems and thus improve
`treatment compliance. The purpose of this study wa
`to evaluate the safety,
`pharmacokinetic, nd pharmacodynamic profile of a newly developed form of depot
`naJtrexone.
`
`Four healthy nonsmokers, who reported no hi tory of dru and alcohol dependence,
`participated in a placebo-controlled, double-blind, outpatient trial. On day one, subjects
`received two s.c. injecrions simultaneously, one in each upper arm (triceps area).
`Injections contained either nalrrexone (52 mg) or placebo microcap ules. An assessment
`b t1ery, consisting of dermatological, physiologic. subjective, and performance measures
`and blood samples for hematology, chemistry. and n ltrexone concentration, was
`completed at pre-injection baseline and n:peated at 4 and 8 hours postdrug and on days 2,
`3, 5, 8, I 1, 15, 22, 29, 36, 50, and 64.
`
`Re ults indicated no tissue irritAtion or infection at the injection sites, and no adver e
`phy ical signs nd symptoms. Laboratory results were norm I. Mean maximal plasma
`nnlttexone concentration of0.93 ng/ml was observed t 24 hours po t·naltrc.llooe. Plasma
`levels declined to about 0.4 nglml at four days post-naltrexone and remained relatively
`saable through day 21.
`
`e, testing will
`.Becnuse the data suggest that this low dose (52 mg) of depot n~trexone is
`be conducted with higher doses to achieve a . u.saained naltrexone plasma concentration of
`1·2 ng/ml.
`AFFlLIA TIONS
`
`Clinical Pharmacology Branch, Addiction Research Center, NIDA, Nnl, Baltimore, MD
`and Medications Development Division, NIDA, NIH, Rockville, MD
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`82
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