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An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Development and Verification of a Full Physiologically Based Pharmacokinetic Model for Sublingual Buprenorphine in
Matthijs W van Hoogdalem1, Ryota Tanaka1, Trevor N Johnson1
1Division of Translational and Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (M.W.v.H., R.T., A.A.V., T.M.); James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio (M.W.v.H.); Certara UK Limited, Sheffield, United Kingdom (T.N.J.); and Department of Pediatrics (A.A.V., T.M.) and Center for Addiction Research (A.A.V., T.M.), College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Abstract:
Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome. The study aimed to develop a full physiologically based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e., untransformed or log transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. SIGNIFICANCE STATEMENT: The physiologically based pharmacokinetic (PBPK) model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for maternal-fetal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome.
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