Kinetics of a naltrexone sustained-release preparation
`
`A biodegradable sustained-release naltrexone bead preparation containing 70% naltrexone in a
`physical mixture with a copolymer of 90% lactic acid and 10% glycolic acid was evaluated in
`three male subjects. Each subject received a 10-mg iv dose of naltrexone HCI and a 63-mg dose
`by subcutaneous implantation of naltrexone beads. Kinetics of naltrexone estimated from the
`intravenous dose indicated a plasma clearance range of 3.] to 3.4 [/min and a t2 range of 1.7
`to 3.7 hr. After bead implantation, average plasma naltrexone levels were maintained at 0.3 to
`0.4 ng/ml and naltrexol levels were at 0.4 to 1.0 ng/ml for a period of approximately | mo,
`during which urine naltrexone and naltrexol levels were about 20 to 30 and 70 to 200 ng/ml. It
`was estimated that approximately 70% to 77% of the dose was absorbed after bead
`implantation. There were no serious adverse effects other than tissue irritation in two of the
`three subjects.
`
`C. N. Chiang, Ph.D., L. E. Hollister, M.D., Akiri Kishimoto, M.D., and
`G. Barnett, Ph.D.* Rockville, Md., and Palo Alto, Calif.
`Division of Preclinical Research, National Institute on Drug Abuse, Rockville, and Veterans
`Administration Hospital, Palo Alto
`
`long-acting
`Naltrexone, a safe and potent
`narcotic antagonist,* ° is currently underclini-
`cal investigation for the treatment of narcotic
`addiction. Because of the need for long-term
`treatment in drug addiction and the problem of
`patient compliance, a sustained-release prep-
`aration that blocks narcotic effects for about a
`month will have an advantage over currentoral
`preparations, which require dosing daily or
`three times a week.® One of the dosage forms
`developed,® biodegradable beads containing
`naltrexone, has been shown in animals to re-
`lease naltrexone and provide pharmacologic ac-
`
`Supported by National Institute on Drug Abuse Grant No, DA-
`00424 and Contract Nos. 271-81-3802 and 271-82-3900.
`Received for publication June 22, 1984; accepted Aug. 9, 1984.
`Reprint requests to: C. N. Chiang, Division of Preclinical Re-
`search, National Institute on Drug Abuse, Rockville, MD 20857.
`*Present address: Laboratory of Mathematical Biology, National
`CancerInstitute, Bethesda, MD 20205.
`
`704
`
`tivity for 1 mo.** ® We report a preliminary
`evaluation of naltrexone beads in man. Since
`the effect of narcotic antagonism was shown to
`correlate with plasma naltrexone levels
`in
`man,’ a kinetic study was performed to charac-
`terize plasma and urine levels of naltrexone and
`its metabolite naltrexol after subcutaneous im-
`plantation of naltrexone beads in man.
`
`Methods
`
`(10
`Naltrexone beads and naltrexone HCl
`mg/ml) solution were provided by the National
`Institute on Drug Abuse. The naltrexone bead is
`a solid solution sphere, 1.5 mm in diameter and
`3.0 mg in weight, composed of 70% naltrexone
`in a physical blend with a copolymer of 90%
`L(+)-lactic acid and 10% glycolic acid. Our
`subjects were three normal healthy men aged 20
`to 37 yr who were given an intravenous injec-
`tion of 10 mg (1 ml) naltrexone and a subcuta-
`
`(cid:36)(cid:51)(cid:50)(cid:55)(cid:40)(cid:59)(cid:3)(cid:40)(cid:59)(cid:43)(cid:44)(cid:37)(cid:44)(cid:55)(cid:3)(cid:20)(cid:19)(cid:20)(cid:28)
`APOTEX EXHIBIT 1019
`(cid:36)(cid:83)(cid:82)(cid:87)(cid:72)(cid:91)(cid:3)(cid:89)(cid:17)(cid:3)(cid:36)(cid:79)(cid:78)(cid:72)(cid:85)(cid:80)(cid:72)(cid:86)
`Apotex v. Alkermes
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:21)(cid:24)(cid:16)(cid:19)(cid:19)(cid:24)(cid:20)(cid:23)
`IPR2025-00514
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` 15326535, 1984, 5, Downloaded from https://ascpt.onlinelibrary.wiley.com/doi/10.1038/clpt.1984.243 by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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` 15326535, 1984, 5, Downloaded from https://ascpt.onlinelibrary.wiley.com/doi/10.1038/clpt.1984.243 by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`

`

` 15326535, 1984, 5, Downloaded from https://ascpt.onlinelibrary.wiley.com/doi/10.1038/clpt.1984.243 by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
`
`

`

` 15326535, 1984, 5, Downloaded from https://ascpt.onlinelibrary.wiley.com/doi/10.1038/clpt.1984.243 by Pennsylvania State University, Wiley Online Library on [22/01/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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