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Advances in Therapy

, Volume 34, Issue 2, pp 560–575 | Cite as

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

  • Muna Albayaty
  • Margareta Linden
  • Håkan Olsson
  • Markus Johnsson
  • Kerstin Strandgården
  • Fredrik Tiberg
Original Research

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.

Keywords

CAM2038 Buprenorphine Opioid dependence Opioid use disorder Pharmacokinetics Sustained release 

Notes

Acknowledgements

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.

Disclosures

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.

Data Availability

The datasets analyzed in the current study are available from the corresponding author on reasonable request.

References

  1. 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.
  2. 2.
    Meyer R, Patel AM, Rattana SK, Quock TP, Mody SH. Prescription opioid abuse: a literature review of the clinical and economic burden in the United States. Popul Health Manag. 2014;17:372–87.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Brady KT, McCauley JL, Back SE. Prescription opioid misuse, abuse, and treatment in the United States: an update. Am J Psychiatry. 2016;173:18–26.CrossRefPubMedGoogle Scholar
  4. 4.
    Kahan M, Srivastava A, Ordean A, Cirone S. Buprenorphine: new treatment of opioid addiction in primary care. Can Fam Physician. 2011;57:281–9.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Khanna IK, Pillarisetti S. Buprenorphine—an attractive opioid with underutilized potential in treatment of chronic pain. J Pain Res. 2015;8:859–70.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Johnson RE, Jaffe JH, Fudala PJ. A controlled trial of buprenorphine treatment for opioid dependence. JAMA. 1992;267:2750–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Ling W, Charuvastra C, Collins JF, et al. Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial. Addiction. 1998;93:475–86.CrossRefPubMedGoogle Scholar
  8. 8.
    Schottenfeld RS, Pakes JR, Oliveto A, Ziedonis D, Kosten TR. Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch Gen Psychiatry. 1997;54:713–20.CrossRefPubMedGoogle Scholar
  9. 9.
    Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry. 1994;151:1025–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Riksheim M, Gossop M, Clausen T. From methadone to buprenorphine: changes during a 10 year period within a national opioid maintenance treatment programme. J Subst Abuse Treat. 2014;46:291–4.CrossRefPubMedGoogle Scholar
  11. 11.
    Lofwall MR, Walsh SL. A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med. 2014;8:315–26.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Gryczynski J, Mitchell SG, Jaffe JH, O’Grady KE, Olsen YK, Schwartz RP. Leaving buprenorphine treatment: patients’ reasons for cessation of care. J Subst Abuse Treat. 2014;46:356–61.CrossRefPubMedGoogle Scholar
  13. 13.
    Tkacz J, Volpicelli J, Un H, Ruetsch C. Relationship between buprenorphine adherence and health service utilization and costs among opioid dependent patients. J Subst Abuse Treat. 2014;46:456–62.CrossRefPubMedGoogle Scholar
  14. 14.
    Tiberg F, Johnsson M, Jankunec M, Barauskas J. Phase behavior, functions, and medical applications of soy phosphatidylcholine and diglyceride lipid compositions. Chem Lett. 2012;41:1090–2.CrossRefGoogle Scholar
  15. 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
  16. 16.
    Tiberg F, Roberts J, Cervin C, et al. Octreotide sc depot provides sustained octreotide bioavailability and similar IGF-1 suppression to octreotide LAR in healthy volunteers. Br J Clin Pharmacol. 2015;80:460–72.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Sigmon SC. Access to treatment for opioid dependence in rural America: challenges and future directions. JAMA Psychiatry. 2014;71:359–60.CrossRefPubMedGoogle Scholar
  18. 18.
    Greenwald MK, Comer SD, Fiellin DA. Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. Drug Alcohol Depend. 2014;144:1–11.CrossRefPubMedGoogle Scholar
  19. 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. 20.
    Bristol-Myers Squibb. Nalorex summary of product characteristics. 2014. https://www.medicines.org.uk/emc/medicine/9281. Accessed 3 Jan 2017.

Copyright information

© Springer Healthcare 2017

Authors and Affiliations

  • Muna Albayaty
    • 1
  • Margareta Linden
    • 2
  • Håkan Olsson
    • 2
  • Markus Johnsson
    • 2
  • Kerstin Strandgården
    • 2
  • Fredrik Tiberg
    • 2
  1. 1.Parexel Early Phase Clinical Unit Level 7Northwick Park HospitalLondonUK
  2. 2.Camurus AB, Ideon Science ParkLundSweden

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