학술논문
A novel long-acting formulation of oral buprenorphine/naloxone produces prolonged decreases in fentanyl self-administration by rhesus monkeys.
Document Type
Academic Journal
Author
Foltin RW; Division on Substance Use Disorders, New York State Psychiatric Institute and Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and Columbia University Irving Medical Center, 1051 Riverside Drive, New York, NY 10032, USA. Electronic address: rwf2@cumc.columbia.edu.; Zale S; Lyndra Therapeutics, Inc., 65 Grove St, Watertown, MA 02472, USA.; Sykes KA; Lyndra Therapeutics, Inc., 65 Grove St, Watertown, MA 02472, USA.; Nagaraj N; Lyndra Therapeutics, Inc., 65 Grove St, Watertown, MA 02472, USA.; Scranton RE; Lyndra Therapeutics, Inc., 65 Grove St, Watertown, MA 02472, USA.; Comer SD; Division on Substance Use Disorders, New York State Psychiatric Institute and Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons and Columbia University Irving Medical Center, 1051 Riverside Drive, New York, NY 10032, USA.
Source
Publisher: Elsevier Country of Publication: Ireland NLM ID: 7513587 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0046 (Electronic) Linking ISSN: 03768716 NLM ISO Abbreviation: Drug Alcohol Depend Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Due to the poor oral bioavailability of buprenorphine, an oral formulation has not been thought possible. Lyndra Therapeutics is developing a once-weekly long-acting oral product containing buprenorphine. We evaluated the efficacy of this formulation in reducing intravenous (i.v.) fentanyl self-administration by three male and three female rhesus monkeys.
Methods: Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days.
Results: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127-265 h*ng/ml. There were no signs of non-specific changes in behavior.
Conclusions: A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).
Competing Interests: Conflict of interest Richard W. Foltin has no conflicts. In the past 3 years, Sandra D.Comer has received research funding from BioXcel Therapeutics and Janssen, and partial salary support through NIDA grants with Go Medical, Intra-cellular Therapies, and Lyndra. In the past 3 years, Dr. Comer has also consulted for: Alkermes, Clinilabs, Mallinckrodt, Nektar, Opiant, and Otsuka. And finally, she has received honoraria from the World Health Organization in compensation for her work on the Expert Committee on Drug Dependence. The remaining authors are or were employed by Lyndra Therapeutics.
(Copyright © 2022 Elsevier B.V. All rights reserved.)
Methods: Buprenorphine HCl and naloxone HCl were co-formulated using an 11:1 ratio of buprenorphine:naloxone in a controlled-release gastric residence formulation administered in an oral capsule (LYN-013). Naloxone was included to determine the feasibility of combining naloxone with buprenorphine in the formulation as an abuse deterrent. Complete fentanyl dose-response functions were determined during each session. The efficacy of single doses of 56/5, 112/10 and 168/15 mg buprenorphine/naloxone in reducing fentanyl self-administration was examined over 13 days.
Results: LYN-013 significantly decreased the rate of responding for fentanyl for 3 days and significantly reduced total intake of fentanyl for 8 days. Time to maximal buprenorphine levels (Tmax) ranged between 56 and 68 h for all 3 doses. The maximal buprenorphine level (Cmax) following 168 mg was 2.3 ng/ml which was significantly greater that those observed for 56 mg (1.22 ng/ml) and 112 mg (1.35 ng/ml). Finally, the area-under-curves (AUCtau) were buprenorphine dose-dependently increased from 88 to 127-265 h*ng/ml. There were no signs of non-specific changes in behavior.
Conclusions: A once-weekly oral buprenorphine/naloxone formulation produced sustained suppression of fentanyl self-administration in monkeys suggesting that oral delivery of buprenorphine with this formulation could provide a new opportunity to treat opioid use disorders (OUD).
Competing Interests: Conflict of interest Richard W. Foltin has no conflicts. In the past 3 years, Sandra D.Comer has received research funding from BioXcel Therapeutics and Janssen, and partial salary support through NIDA grants with Go Medical, Intra-cellular Therapies, and Lyndra. In the past 3 years, Dr. Comer has also consulted for: Alkermes, Clinilabs, Mallinckrodt, Nektar, Opiant, and Otsuka. And finally, she has received honoraria from the World Health Organization in compensation for her work on the Expert Committee on Drug Dependence. The remaining authors are or were employed by Lyndra Therapeutics.
(Copyright © 2022 Elsevier B.V. All rights reserved.)