A Physiologically Based Pharmacokinetic Modeling Approach to Predict Buprenorphine Pharmacokinetics following Intravenous & Sublingual Administration

Abstract

Introduction

Opioid dependence is associated with high morbidity and mortality. Buprenorphine(BUP) is approved by the FDA to treat opioid dependence. There is a lack of clear consensus on appropriate dosing of BUP due to inter-patient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of this study is to build and validate robust physiologically-based-pharmacokinetic(PBPK) models for intravenous(IV) and Sublingual(SL) BUP as a first-step to optimize BUP pharmacotherapy.

Methods

BUP-PBPK modeling and simulations were performed using SimCyp® by incorporating physiochemical properties of BUP, establishing Inter-System Extrapolation Factors(ISEF) based In-Vitro In-Vivo Extrapolation(IVIVE) methods to extrapolate in-vitro enzyme activity data, and using tissue specific Kp estimations. Published data on IV and SL-BUP in opioid and non-opioid dependent patients was used to build the models. Fourteen model-naïve BUP-PK datasets were used for inter-study and intra-study validations.

Results

IV and SL-BUP-PBPK models developed are robust in predicting multi-compartment disposition of BUP over a dosing range of 0.3-32 mg. Predicted plasma concentration-time profiles in virtual patients are consistent with reported data across 5 IV-single dose, 5 SL-single dose and 4 SL-multiple dose studies. All PK parameter predictions were within 75%-137% of the corresponding observed data. The model is not robust enough for DDI assessment. The model developed predicted brain exposure of BUP to be about 4 times higher than that of BUP in plasma.

Conclusion

The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on varying demographic, physiological and pathological characteristics of patients.

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