Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combi
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ORIGINAL RESEARCH ARTICLE
Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials Aksana K. Jones1 · Eliford Ngaimisi2 · Mathangi Gopalakrishnan2 · Malcolm A. Young1 · Celine M. Laffont1 Accepted: 16 October 2020 © The Author(s) 2020
Abstract Background BUP-XR (a.k.a. RBP-6000 or SUBLOCADE™) is an extended-release subcutaneous buprenorphine formulation for the treatment of opioid use disorder. BUP-XR was designed to provide sustained buprenorphine exposure throughout the monthly dosing interval, at concentrations sufficient to control all aspects of the disease (withdrawal, craving, and blockade of opioid subjective effects). Objectives To characterize the population pharmacokinetics of BUP-XR based on phase II and phase III data and to evaluate whether target therapeutic concentrations were reached with the dosing regimens evaluated in the phase III program. Methods The population pharmacokinetic analysis included 570 subjects with opioid use disorder who received up to 12 monthly BUP-XR injections following induction with sublingual buprenorphine. Results In phase III studies, target therapeutic concentrations of buprenorphine were achieved from the first injection and maintained over the entire treatment duration. Buprenorphine plasma concentration–time profiles were well described by a two-compartment model, with first-order absorption for sublingual buprenorphine and a dual absorption submodel for BUPXR. A covariate analysis evaluated the effects of subjects’ demographic characteristics, laboratory data, and genetic status regarding buprenorphine-metabolizing enzymes. Only two covariates, body mass index and body weight, were retained in the final model. Overall, their effects were not of sufficient magnitude to justify a dose adjustment. Finally, pharmacokinetic simulations showed that buprenorphine plasma concentrations decreased slowly after discontinuation of treatment and that a 2-week occasional delay in dosing would not impact efficacy, which translated into labeling claims. Discussion In conclusion, the present analysis led to the development of a robust population pharmacokinetic model and confirms the ability of BUP-XR to deliver and maintain therapeutic plasma concentrations over the entire treatment duration.
Key Points
Aksana K. Jones and Eliford Ngaimisi contributed equally to the article. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40262-020-00957-0) contains supplementary material, which is available to authorized users. * Celine M. Laffont [email protected] 1
Indivior Inc., 10710 Midlothian Turnpike, Suite 125, North Chesterfield, VA 23235, USA
Center for Translational Medicine, University of Maryland, Baltimore, USA
2
The current analysis confirms the ability of the BUP-XR formulation to deliver and maintain therapeutic plasma concentrations of buprenorphine throughout the monthly dosing interval. A r
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