When special populations intersect with drug–drug interactions: Application of physiologically‐based pharmacokinetic modeling in pregnant populations

Abstract

Pregnancy results in significant physiological changes that vary across trimesters and into the postpartum period, and may result in altered disposition of endogenous substances and drug pharmacokinetics. Pregnancy represents a unique special population where physiologically‐based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms without subjecting pregnant women or their fetuses to extensive clinical studies. A critical review of applications of pregnancy PBPK models (pPBPK) was conducted to understand its current status for prediction of drug exposure in pregnant populations and to identify areas of further expansion. Evaluation of existing pPBPK modeling efforts highlighted improved understanding of cytochrome P450 (CYP)‐mediated changes during pregnancy and identified knowledge gaps for non‐CYP enzymes and the physiological changes of the postpartum period. Examples of the application of pPBPK beyond simple dose regimen recommendations are limited, particularly for prediction of drug–drug interactions (DDI) or differences between genotypes for polymorphic drug metabolizing enzymes. A raltegravir pPBPK model implementing UGT1A1 induction during the second and third trimesters of pregnancy was developed in the current work and verified against clinical data. Subsequently, the model was used to explore UGT1A1‐related DDI risk with atazanavir and rifampicin along with the effect of enzyme genotype on raltegravir apparent clearance. Simulations of pregnancy‐related induction of UGT1A1 either exacerbated UGT1A1 induction by rifampicin or negated atazanavir UGT1A1 inhibition. This example illustrated the advantages of pPBPK modeling for mechanistic evaluation of complex interplays of pregnancy‐ and drug‐related effects in support of model‐informed approaches in drug development.

Clinical Implications of Altered Drug Transporter Abundance/Function and PBPK Modeling in Specific Populations: An ITC Perspective

“…Such dose adjustments may be more relevant when considering the magnitude of the DDI, which may differ compared with non-pregnant individuals, as illustrated in the case of metabolism. 20 Increased activity of renal OCT2/MATE1-2 K transporters in the second and third trimesters in pregnant women was suggested based on metformin as a probe drug, with up to 77% increase in the secretion clearance. 87,88 Although changes in protein abundances have been noted for certain hepatic transporters in pregnant mice, there have been limited reports regarding the clinical relevance of these changes.…”

“…The renal secretory activity of OAT1/2/3 transporter probe substrate drugs in pregnant women 86 indicated >2‐fold increase in drug exposure in certain trimesters for either OAT1, OAT2, or OAT3 relative to non‐pregnant women, and indicated potential requirements for dose adjustment for these drugs. Such dose adjustments may be more relevant when considering the magnitude of the DDI, which may differ compared with non‐pregnant individuals, as illustrated in the case of metabolism 20 . Increased activity of renal OCT2/MATE1‐2 K transporters in the second and third trimesters in pregnant women was suggested based on metformin as a probe drug, with up to 77% increase in the secretion clearance 87,88 .…”

“…PBPK modeling can also support the inclusion of the patients in late‐phase clinical trials to inform on the need for dose adjustments 5,6 . Applications of PBPK models in diseased and specific populations is a fast‐growing area 16,20,21 and has demonstrated promising predictive performance in certain patient populations. In many instances, existing examples are for drugs predominantly cleared by metabolism, as evidenced by recent PBPK modeling in renally impaired (RI) patients 22 or in pediatric patients with spinal muscular atrophy 16 .…”

The Perks and Drawbacks of Physiologically-Based Pharmacokinetic Modeling

“…Pharmacokinetic (PK) parameter calculations through PBPK simulation can also be used for dosing optimization and safety margins predictions 5,6 . These models are potentially useful in drug-drug interaction (DDI), pediatric and special population studies representing a costeffective tool that addresses of some ethical challenges associated with clinical trials in sensitive populations (e.g., pregnant women, organ transplant patients, etc) and potentially useful for drugs with a narrow therapeutic window [6][7][8][9][10][11][12] . Aside from the pharmacological scope, PBPK models represent a safe tool for studying substances with little or no therapeutical value that are rarely submitted to clinical studies, such as drugs of abuse or toxic occupational chemicals; hence they can be used for forensic and/or regulatory purposes [13][14][15][16] .…”

Developing New Treatments for COVID-19 through Dual-Action Antiviral/Anti-Inflammatory Small Molecules and Physiologically Based Pharmacokinetic Modeling

“…In their work, Sychterz et al, used PBPK modeling to examine the UGT1A1-related DDI risk with raltegravir and atazanavir in pregnant populations [ 54 ]. They found that the induction of UGT1A1 by pregnancy is negated by atazanavir UGT1A1 inhibition.…”