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)
- Sublingual buprenorphine is used in the management of opioid use
disorder in adults, including pregnant women.
- Bioavailability is dose- and formulation-dependent, but this intricacy
has not yet been incorporated into any physiologically-based
pharmacokinetic (PBPK) model.
- Neonatal opioid withdrawal syndrome (NOWS) may arise in newborns
prenatally exposed to opioids such as buprenorphine.
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