Invited ArticleA review of pregnancy-induced changes in opioid pharmacokinetics, placental transfer, and fetal exposure: Towards fetomaternal physiologically-based pharmacokinetic modeling to improve the treatment of neonatal opioid withdrawal syndrome
Introduction
Pharmacokinetic (PK) models are mathematical tools that describe drug disposition, which can be used to predict plasma or tissue concentrations at a specific dose (Mould and Upton, 2012, Mould and Upton, 2013). PK models emerged as a cascade of increasing complexity. Conventional population PK models reduce the human body to a central compartment, possibly linked to one or two peripheral compartments, where each compartment does not directly represent a physiological organ. Population PK models are empirically developed (also known as a “top-down” approach), meaning that observed concentration-time data are used to estimate underlying PK parameters. Although still widely used and useful to date, the empirical model's limited anatomical and biological foundation complicates extrapolation to physiological conditions not observed in the study population whose data were used for model development. Hence, physiologically-based pharmacokinetic (PBPK) models materialized (Rowland, Peck, & Tucker, 2011). Although these models are similarly compartmentalized, the compartments reflect actual tissue and organ spaces with corresponding realistic volumes, enabling more comprehensive and mechanism-based modeling.
Through pioneering work by Teorell, the foundation for PBPK modeling was laid as early as 1937 (Teorell, 1937a, Teorell, 1937b). PBPK modeling rose to prominence in the 1960s and 1970s (Himmelstein & Lutz, 1979), and has since been implemented in a variety of clinical areas, such as in supporting dose selection in neonatal and pediatric populations (Strougo et al., 2012; Wagner et al., 2015), evaluating drug-drug interactions (Vieira et al., 2014), and informing clinical trial design (Jones et al., 2015). PBPK models conjoin human body characteristics (e.g., weight, age, blood flow, organ size, enzyme abundance) and drug physicochemical properties (e.g., logP, pKa, blood binding, permeability). In contrast to empirical PK models, PBPK models are developed in a “bottom-up” manner, in which fundamental in vitro data are scaled to conceptualize in vivo PK parameters (also called in vitro-in vivo extrapolation [IVIVE]). In practice, clinical observations are then generally used to validate the PBPK model, optimize physiological or drug-related parameters, or estimate the value of those unknown, in an overall “middle-out” approach (Jamei, Dickinson, & Rostami-Hodjegan, 2009).
Drug disposition in pediatric and neonatal subjects has historically been understudied due to practical concerns in conducting such clinical studies. Still, rapid physiological development and maturation, which inherently affect drug disposition, warrant characterization of pediatric and neonatal PK to identify age-appropriate doses to ensure drug safety and efficacy. Over the past decade, PBPK modeling has emerged as an elegant approach to assess drug behavior in neonates, infants, and children (Verscheijden, Koenderink, Johnson, de Wildt, & Russel, 2020). Another patient group that has historically been excluded from drug research is pregnant women. Although the motivation to do so is evident, this has led to insufficient PK and safety data to guide dosing in pregnant or breastfeeding women for an overwhelming majority of drugs (Carvalho & Wong, 2015; McCormack & Best, 2014). This creates a conundrum for physicians and patients, as it has been shown that in the United States (US) between 34.4 and 39.0% of pregnant women use one or more medications (excluding vitamins and minerals) in the first, second, or third trimester regardless (Daw, Hanley, Greyson, & Morgan, 2011). Pregnant women do not exhibit similar drug disposition as their nonpregnant female and male counterparts typically enrolled in clinical trials (Pariente et al., 2016). Moreover, women carry a vulnerable developing fetus during gestation that needs to be protected from toxic effects of certain xenobiotics. Toxicity is, in part, dependent on placental transfer of the compound, as well as maternal and fetal PK, which rapidly change during gestation. Emerging studies (George et al., 2020; Szeto, Le Merdy, Dupont, Bolger, & Lukacova, 2021) reveal that PBPK models can incorporate pregnancy-related physiological changes and help achieve a better understanding of drug behavior in this special population. In this review, pregnancy-induced changes in opioid PK, placental opioid transfer, and fetal opioid disposition are discussed in the context of neonatal opioid withdrawal syndrome (NOWS). In addition, the implementation of these different elements in PBPK models is described.
Section snippets
Neonatal opioid withdrawal syndrome (NOWS)
The opioid epidemic continues to ravage the US. In 2019, 49,860 people died from opioid overdoses, amounting to an average of one death every ten minutes, which is a six-fold increase since 2000 (Hedegaard, Miniño, & Warner, 2020). The coronavirus disease 2019 (COVID-19) pandemic likely further aggravated the opioid epidemic (Ochalek, Cumpston, Wills, Gal, & Moeller, 2020; Wainwright et al., 2020). Recently, it was found that 6.6% of women self-reported opioid use during pregnancy, of which
Physiological changes affecting opioid disposition during pregnancy
Pregnancy induces a plethora of physiological and anatomical changes in gravid women, including altered drug absorption, and increased volume of distribution, renal blood flow, and hepatic blood flow. These changes and their effect on PK in general have been described previously in great detail (Abduljalil, Furness, Johnson, Rostami-Hodjegan, & Soltani, 2012; Tasnif, Morado, & Hebert, 2016). In this article, the effect of pregnancy-induced physiological changes on specifically the PK of
Anatomy of the placenta
The placenta is the interface between the maternal and fetal circulation and supplies the fetus with oxygen and nutrients, while simultaneously clearing metabolic waste products from the fetal blood. It is a unique organ as it is the only human organ that has a transient existence, arising during early pregnancy and expelling itself following parturition once its purpose has been fulfilled. The placenta acts as a protective barrier for some compounds, but many xenobiotics, driven by the
Towards prediction of fetal opioid disposition and NOWS severity
Thus far, the physiological changes during pregnancy that affect opioid PK and the extent of placental opioid transfer from maternal to fetal circulation have been discussed. Moreover, successful incorporation of these processes in pregnancy PBPK models has been described. Such pregnancy PBPK models can be used to characterize fetal opioid exposure. However, to attain insight into fetal opioid disposition (e.g., metabolism of opioids by the fetus itself and distribution throughout fetal
Conclusion
Pregnancy induces a plethora of physiological and metabolic changes that influence maternal PK. For opioids and their metabolites specifically, promoted activity of CYP and UGT enzymes, increased renal excretion, and, conceivably, reduced biliary secretion are key drivers of altered PK during gestation. These pregnancy-induced changes are not static; rather, conception initiates a cascade of modifications and adaptations that are constantly developing, with some effects possibly
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.
Acknowledgments
M.W.v.H. was supported by the Ritschel Doctoral Fellowship of the University of Cincinnati. T.M. has received a research grant from the Center for Clinical and Translational Science and Training (CCTST); National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 2UL1TR001425-05A1.
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