A Population Pharmacokinetic and Pharmacodynamic Modelling Approach to Support the Clinical Development of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Dependence
- 766 Downloads
Background and Objectives
This study implemented pharmacokinetic/pharmacodynamic modelling to support the clinical development of RBP-6000, a new, long-acting, sustained-release formulation of buprenorphine for the treatment of opioid dependence. Such a formulation could offer advantages over existing buprenorphine pharmacotherapy by improving patient compliance and reducing the diversion of the product.
A population pharmacokinetic model was developed using 36 opioid-dependent subjects who received single subcutaneous doses of RBP-6000. Another pharmacokinetic/pharmacodynamic model was developed using μ-opioid receptor occupancy (µORO) data to predict efficacy of RBP-6000 after repeated doses. It was also assessed how buprenorphine plasma concentrations were correlated with opioid withdrawal symptoms and hydromorphone agonist blockade data from 15 heroin-dependent subjects.
The resulting pharmacokinetic model accurately described buprenorphine and norbuprenorphine plasma concentrations. A saturable maximum effect (E max) model with 0.67 ng/mL effective concentration at 50 % of maximum (EC50) and 91 % E max best described µORO versus buprenorphine plasma concentrations. Linear relationships were found among µORO, withdrawal symptoms and blockade of agonist effects.
Previously published findings have demonstrated µORO ≥70 % is needed to achieve withdrawal suppression and blockade of opioid agonist subjective effects. Model simulations indicated that a 200 mg RBP-6000 dose should achieve 2–3 ng/mL buprenorphine average concentrations and desired efficacy.
KeywordsBuprenorphine Withdrawal Symptom Hydromorphone Opioid Dependence Objective Function Value
The authors would like to acknowledge Bradley Vince, DO, President and Medical Director at Vince & Associates (10103 Metcalf Avenue, Overland Park, KS 66212, USA) for patient recruitment in this study.
Conflict of Interest/Disclosure
At the time this manuscript was submitted for publication, A.F. Nasser, C. Heidbreder, P.J. Fudala and B. Zheng were full-time employees of Reckitt Benckiser Pharmaceuticals Inc. M.K. Greenwald was a full-time employee of Wayne State University, and was a paid consultant for Reckitt Benckiser Pharmaceuticals Inc. R. Gomeni was a paid consultant for Reckitt Benckiser Pharmaceuticals Inc.
- 4.Kochanek KD, Xu J, Murphy SL, Miniño AM, Kung H-C. Deaths: preliminary data for 2009. Natl Vital Stat Rep. 2011;59:1–51.Google Scholar
- 5.Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network (2011). National estimates of drug-related emergency department visits. HHS publication no. (SMA) 13-4760, DAWN series D-39. Rockville: Substance Abuse and Mental Health Services Administration; 2013.Google Scholar
- 7.SUBOXONE® sublingual film label. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022410s015lbl.pdf. Accessed 31 Jan 2014.
- 10.R Foundation for Statistical Computing (2009). R: a language and environment for statistical computing. http://www.R-project.org. Accessed 14 Dec 2013.
- 11.Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM user’s guides, 1989–2013. Ellicott City: Icon Development Solutions; 2013.Google Scholar
- 14.Food and Drug Administration (1999). Guidance for industry: population pharmacokinetics. http://www.fda.gov/downloads/Drugs/Guidances/UCM072137.pdf. Accessed 16 Dec 2013.
- 16.Kobayashi K, et al. Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Disp. 1998;26:818–21.Google Scholar
- 21.Greenwald MK, Steinmiller CL. Imaging opioid receptors: applications to substance use disorders. In: Dean R, Negus SS, Bilsky E, editors. Opioid receptors and antagonists: from bench to clinic. New York: Humana Press 2009; p. 45–65.Google Scholar
- 22.Gomeni R, Heidbreder C, Fudala PJ, Nasser AF. A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-release formulation of risperidone. J Clin Pharmacol. 2013;53:1010–9.PubMedCrossRefGoogle Scholar