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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 (C max ), and time to reach C max (T max ) 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 C max equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for T max 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., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal-fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal-fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal-fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity.

Physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to study pharmacokinetics (PK) in special populations, such as pregnant women, fetuses, and newborns, where practical hurdles severely limit the study of drug behavior. PK in pregnant women is variable and everchanging, differing greatly from that in their nonpregnant female and male counterparts typically enrolled in clinical trials. PBPK models can accommodate pregnancy-induced physiological and metabolic changes, thereby providing mechanistic insights into maternal drug disposition and fetal exposure. Fueled by the soaring opioid epidemic in the United States, opioid use during pregnancy continues to rise, leading to an increased incidence of neonatal opioid withdrawal syndrome (NOWS). The severity of NOWS is influenced by a complex interplay of extrinsic and intrinsic factors, and varies substantially between newborns, but the extent of prenatal opioid exposure is likely the primary driver. Fetomaternal PBPK modeling is an attractive approach to predict in utero opioid exposure. To facilitate the development of fetomaternal PBPK models of opioids, this review provides a detailed overview of pregnancy-induced changes affecting the PK of commonly used opioids during gestation. Moreover, the placental transfer of these opioids is described, along with their disposition in the fetus. Lastly, the implementation of these factors into PBPK models is discussed. Fetomaternal PBPK modeling of opioids is expected to provide improved insights in fetal opioid exposure, which allows for prediction of postnatal NOWS severity, thereby opening the way for precision postnatal treatment of these vulnerable infants., Competing Interests: Declaration of Competing Interest S.L.W. has received a research grant from Chiesi Pharmaceuticals and a consulting fee from Braeburn Pharmaceuticals. All other authors declared no competing interests for this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC 0-∞ ), peak concentration (C max ), and time to reach peak concentration (T max ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)