Pharmacokinetic Evaluation of Once-Weekly and Once-Monthly Buprenorphine Subcutaneous Injection Depots (CAM2038) Versus Intravenous and Sublingual Buprenorphine in Healthy Volunteers Under Naltrexone Blockade: An Open-Label Phase 1 Study
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CAM2038 q1w (once weekly) and q4w (once monthly) are investigational buprenorphine subcutaneous (SC) formulations based on FluidCrystal® injection depot technology. These two drug products are being developed for opioid dependence treatment, with a target for once-weekly and once-monthly SC dosing. The rationale for developing two products with different dosing frequencies is that treatment strategies/routines, and hence different treatment preferences, can vary between patients, different stages of opioid maintenance treatment, and countries. This study evaluated the pharmacokinetics and safety of buprenorphine and norbuprenorphine following administration of CAM2038 q1w or q4w versus active controls.
Healthy volunteers were randomized to five treatment groups. All received a single intravenous dose of buprenorphine 600 µg, followed post-washout by a single dose of CAM2038 q4w 96 mg, a single dose of CAM2038 q4w 192 mg, or sublingual buprenorphine 8, 16, or 24 mg daily for 7 days, followed post-washout by a single dose of CAM2038 q4w 64 or 128 mg or four repeated weekly doses of CAM2038 q1w 16 mg. All subjects received daily naltrexone.
Eighty-seven subjects were randomized. Median buprenorphine t max after CAM2038 q4w was 4–10 h (24 h for CAM2038 q1w); mean terminal half-life was 19–25 days (5 days for CAM2038 q1w). CAM2038 q4w showed dose-proportional buprenorphine release, with similar exposure to repeat-dose CAM2038 q1w at comparable monthly dose level. Both CAM2038 formulations showed complete absolute bioavailability of buprenorphine and 5.7- to 7.7-fold greater buprenorphine bioavailability versus sublingual buprenorphine. CAM2038 q1w and q4w were well tolerated; subjects’ acceptance was higher for CAM2038 than for sublingual buprenorphine 1 h post-dose.
The pharmacokinetic profiles of CAM2038 q1w and q4w versus sublingual buprenorphine support expected treatment efficacy with once-weekly and once-monthly dosing, respectively. CAM2038 formulations were safe and showed good local tolerability.
Trial registration: ISRCTN24987553.
Funding: Camurus AB.
KeywordsCAM2038 Buprenorphine Opioid dependence Opioid use disorder Pharmacokinetics Sustained release
This study was funded by Camurus AB. Richard Ogilvy-Stewart, an employee of Mudskipper Business Limited, provided assistance with writing/formatting/proofreading/collation of the author comments and this assistance was funded by Camurus AB. Article-processing charges were funded by Camurus AB. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.
Margareta Linden is a full-time employee of Camurus AB. Håkan Olsson is a full-time employee of Camurus AB. Markus Johnsson is a full-time employee of Camurus AB. Kerstin Strandgården is a full-time employee of Camurus AB. Fredrik Tiberg is a full-time employee of Camurus AB. Muna Albayaty has nothing to disclose.
Compliance with Ethics Guidelines
The trial was conducted in compliance with, International Conference on Harmonisation, Good Clinical Practice guidelines and the 1964 Declaration of Helsinki, and its later amendments. The protocol, subject information sheet and consent sheet were approved by the local independent ethics committee (NRES Committee North East, York, UK) and The Medicines and Healthcare Products Regulatory Agency; written informed consent was obtained from all individual participants included in the study. The study is registered with the ISRCTN registry (http://www.isrctn.com/ISRCTN24987553). The study was conducted at the Parexel Early Phase Clinical Unit at Northwick Hospital in London, UK, in 2014–2015.
The datasets analyzed in the current study are available from the corresponding author on reasonable request.
- 1.United Nations Office on Drugs and Crime. World drug report 2014. 2014. https://www.unodc.org/documents/wdr2014/World_Drug_Report_2014_web.pdf. Accessed 3 Jan 2017.
- 15.Tiberg F, Johnsson M, Nistor C, Joabsson F. Self-assembling lipid formulations. In: Wright JC, Burgess DJ, editors. Long-acting injections and implants. New York: Springer; 2012. p. 315–334.Google Scholar
- 19.Endo Pharmaceuticals. Belbuca—buprenorphine hydrochloride film. Highlights of prescribing information. 2015. http://www.endo.com/File%20Library/Products/Prescribing%20Information/BELBUCA_prescribing_information.html. Accessed 3 Jan 2017.
- 20.Bristol-Myers Squibb. Nalorex summary of product characteristics. 2014. https://www.medicines.org.uk/emc/medicine/9281. Accessed 3 Jan 2017.