Gestational changes in buprenorphine exposure: A physiologically-based pharmacokinetic analysis

Abstract

Aims: Buprenorphine (BUP) is approved by the US Food and Drug Administration for the treatment of opioid addiction. The current dosing regimen of BUP in pregnant women is based on recommendations designed for nonpregnant adults. However, physiological changes during pregnancy may alter BUP exposure and efficacy. The objectives of this study were to develop a physiologically-based pharmacokinetic (PBPK) model for BUP in pregnant women, to predict changes in BUP exposure at different stages of pregnancy, and to demonstrate the utility of PBPK modelling in optimizing BUP pharmacotherapy during pregnancy.

Methods: A full PBPK model for BUP was initially built and validated in healthy subjects. A fetoplacental compartment was included as a combined compartment in this model to simulate pregnancy induced anatomical and physiological changes. Further, gestational changes in physiological parameters were incorporated in this model. The PBPK model predictions of BUP exposure in pregnancy and during the postpartum period were compared to published data from a prospective clinical study.

Results: The predicted BUP plasma concentration-time profiles in the virtual pregnant populations are consistent with the observed data in the 2^nd and 3^rd trimesters, and the postpartum period. The differences in the predicted means of dose normalized area under the plasma drug concentration-time curve up to 12 h, average concentration and maximum concentration were within ±25% of the corresponding observed means with the exception of average concentration in the 3^rd trimester (-26.3%).

Conclusion: PBPK model-based simulation may be a useful tool to optimize BUP pharmacotherapy during pregnancy, obviating the need to perform pharmacokinetic studies in each trimester and the postpartum period that normally require intensive blood sampling.

Keywords: PBPK; buprenorphine; opioid dependence; pharmacokinetics; pregnancy.

Figure 1

Quantitative mass balance diagram describing buprenorphine (BUP) absorption, distribution, metabolism and excretion after sublingual and intravenous (IV) administration. BUPG, Buprenorphine glucuronide; NBUP, Nor‐buprenorphine; NBUPG, Nor‐buprenorphine glucuronide

Figure 2

Sensitivity analysis to simulate the impact of the abundance of CYPs, UGTs and renal function on buprenorphine total clearance

Figure 3

Predicted mean concentration–time profiles at steady‐state following administration of 8 mg sublingual twice daily buprenorphine during 1st trimester, 2nd trimester, 3rd trimester, and postpartum in 100 virtual female subjects spread across10 trials

Figure 4

Predicted and observed dose normalized concentration–time profiles at steady‐state following administration sublingual twice daily buprenorphine. A, B, and C represent interstudy validation by plotting mean predictions, 5th–95th percentiles of predictions against clinical observed mean concentrations during 2nd trimester, 3rd trimester, and postpartum respectively as observed by Bastian et al. 19

Figure 5

Predicted and observed concentration–time profiles at steady‐state following administration of 8 mg sublingual twice daily buprenorphine. A, B, and C represent interstudy validation by plotting mean predictions, 5th ‐95th percentiles of predictions against clinical observed mean concentrations, and observed individual concentrations during 2nd trimester (Figure 4A), 3rd trimester (Figure 4B), and postpartum (Figure 4C) as reported by Bastian et al. 19

Figure 6

Percent of 100 virtual subjects with buprenorphine plasma concentration above 1 ng ml^–1 in one dosing interval at steady‐state following administration of 8 mg sublingual twice daily during postpartum, 1^st, 2^nd, 3^rd trimester