Development and validation of a full physiologically-based pharmacokinetic model for sublingual buprenorphine that accounts for nonlinear bioavailability
Matthijs W. van Hoogdalem,1,2 Trevor N. Johnson,3 Alexander A. Vinks,1,4,5Tomoyuki Mizuno1,4,5,*
1Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA;
2James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA;
3Certara UK Limited, Sheffield, UK;
4Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA;
5Center for Addiction Research, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
*Correspondence: Tomoyuki Mizuno. Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 6018, Cincinnati, OH 45229, USA.
Telephone: +1 (513) 636-0912. Email: tomoyuki.mizuno@cchmc.org
Principal Investigator statement: No Principal Investigator is listed as no interventions were performed with human subjects/patients in this study.
Conflict of interest statement: T.N.J. is an employee of Certara UK Limited, Simcyp Division. All other authors declared no competing interests for this work.
Funding information: The project described was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH), under Award Number 2UL1TR001425-05A1, and the Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledge & Research Coordination Center (KRCC) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), under Award Number 1P30HD106451. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH and the NICHD. M.W.v.H. was supported by the Rieveschl/Parke-Davis Doctoral Candidacy Scholarship of the University of Cincinnati.
Data availability statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
Keywords : buprenorphine, physiologically-based pharmacokinetic modeling, opioid use disorder
Word count : 3378/4000 words
Table count : 4 (preferably no more than 8 figures and tables)
Figure count : 4 (preferably no more than 8 figures and tables)
What is already known about this subject: (51/50 words)
What this study adds: (45/50 words)
By incorporating nonlinear absorption, the PBPK model developed in this study adequately predicts dose- and formulation-dependent buprenorphine pharmacokinetics.
The developed model will serve as the foundation for fetomaternal PBPK modeling, which will allow conceptualization of prenatal buprenorphine exposure and its influence on postnatal NOWS severity.
Abstract (248/250 words)
Aim: Sublingual buprenorphine is used in the treatment of opioid use disorder (OUD) and neonatal opioid withdrawal syndrome (NOWS). The aim of this study was to develop a full physiologically-based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine.
Methods: Simcyp (v21.0) was used for model construction. Linear regression modeling was explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for validation. The PBPK model’s predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O ratios) area under the curve (AUC), apparent clearance (CL/F), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range.
Results: 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, CL/F, Cmax, and Tmax equaling 0.99 (0.86–1.12), 1.04 (0.92–1.18), 1.24 (1.09–1.40), and 1.07 (0.95–1.20), respectively.
Conclusion: A fully validated PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. The model forms the foundation on which a fetomaternal PBPK model for buprenorphine can be built. Fetomaternal PBPK modeling will allow conceptualization of prenatal buprenorphine exposure and investigation of its influence on postnatal NOWS severity.
Introduction
The opioid epidemic continues to worsen and expand across the United States. Synthetic opioids, especially illicitly manufactured fentanyl, are now the leading cause of drug overdose deaths. Between 2013 and 2019, the synthetic opioid-involved death rate increased more than 10-fold, from 1.0 to 11.4 per 100,000.1 Buprenorphine, administered as a sublingual tablet or solution, is used in the management of opioid use disorder (OUD). Buprenorphine acts as a partial agonist at the μ opioid receptor,2 as an antagonist at δ and κ opioid receptors,3,4 and as a full agonist at the nociceptin/orphanin FQ (NOP) opioid receptor.5This intricate pharmacological profile gives rise to buprenorphine’s more desirable clinical properties compared to other opioids, such as lower abuse potential and reduced likelihood of fatal respiratory depression.6 Among Medicaid enrollees diagnosed with OUD, the use of buprenorphine increased from 28.1% to 37.3% between 2014 and 2018, making it the most prescribed medication to treat OUD.7
Opioid use during pregnancy is not uncommon. In 2019, 6.6% of pregnant women self-reported use of prescription opioids, of which 21.2% disclosed opioid misuse.8 Newborns prenatally exposed to opioids are at risk of developing neonatal opioid withdrawal syndrome (NOWS) after birth. NOWS is characterized by gastrointestinal dysfunction and neurologic excitability,9 and requires pharmacological treatment in those neonates whose symptoms are otherwise insufficiently controlled.10 Sublingually administered buprenorphine is an emerging treatment for NOWS,11 but current dosing strategies have been empirically established and lack a robust pharmacokinetic (PK) and pharmacodynamic (PD) rationale. Neonatal buprenorphine PK is highly variable,12-14 and recent physiologically-based pharmacokinetic (PBPK) modeling and simulation by our group indicated variability is likely driven by differences in the extent of sublingual absorption, biliary clearance, and cytochrome P450 (CYP) 3A4 activity, especially early in life.15Strategies to improve the treatment of NOWS with buprenorphine include further improving our understanding of the complex PK/PD relationship and subsequently adjusting the starting dose to the expected PK profile of the neonate. Additionally, initial dosing could be tailored to the anticipated NOWS severity.
The severity of NOWS differs greatly between affected neonates, but symptoms tend to be more severe in newborns born at term,16 whose mothers used tobacco during pregnancy,17,18 and those who had greater opioid exposure in utero .19 Estimating the extent of prenatal opioid exposure is challenging. Intuitively, fetal opioid exposure may strongly correlate with maternal intake, but studies have failed to demonstrate a consistent relationship between maternal OUD medication dose and postnatal NOWS severity.17,20-22This may be, in part, explained by the everchanging nature of maternal opioid PK during pregnancy and the likelihood that fetuses are more vulnerable to opioid effects at certain points during gestation.19 Fetomaternal PBPK modeling offers a comprehensive framework that can incorporate the kaleidoscopic interplay of maternal and fetal factors that ultimately dictate prenatal opioid exposure. This, in turn, can open the way for precision treatment of NOWS based on the prenatally modeled severity.
Accurately predicting buprenorphine PK following sublingual administration is challenging since bioavailability is dependent on the formulation (tablet vs . solution)23-27 and decreases with dose.26,28,29 Several PBPK models for sublingual buprenorphine have been developed to date, but none have adequately integrated nonlinear bioavailability. Kalluri et al . constructed a full PBPK model,30 which was later expanded to a pregnancy PBPK model,31 but others were not able to recreate these models due to the ambiguous description of sublingual absorption.32 Our group developed a neonatal minimal PBPK model,15 which was based on a model developed by Johnson et al., 33 but given the neonatal application, the model was only validated for low doses, and does not accurately capture reduced bioavailability with higher doses. To lay a strong foundation for planned fetomaternal PBPK modeling, the aim of the present study was to develop a full PBPK model for buprenorphine that can adequately describe dose- and formulation-dependent bioavailability following sublingual administration.
Methods