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 [5]. This 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 [15]. Strategies 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, 20-22]. This 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. [30] constructed a full PBPK model, 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.
MATERIALS AND METHODS
PBPK model development
A full PBPK model for buprenorphine was constructed and validated using Simcyp (v21.0; Simcyp Limited, Sheffield, UK). A schematic representation of the PBPK model is shown in Figure 1. Drug physiochemical and physiological parameters used to build the PBPK model are shown in Table 1 [33-45].