A Simplified PBPK Modeling Approach for Prediction of Pharmacokinetics of Four Primarily Renally Excreted and CYP3A Metabolized Compounds During Pregnancy

Abstract

During pregnancy, a drug's pharmacokinetics may be altered and hence anticipation of potential systemic exposure changes is highly desirable. Physiologically based pharmacokinetics (PBPK) models have recently been used to influence clinical trial design or to facilitate regulatory interactions. Ideally, whole-body PBPK models can be used to predict a drug's systemic exposure in pregnant women based on major physiological changes which can impact drug clearance (i.e., in the kidney and liver) and distribution (i.e., adipose and fetoplacental unit). We described a simple and readily implementable multitissue/organ whole-body PBPK model with key pregnancy-related physiological parameters to characterize the PK of reference drugs (metformin, digoxin, midazolam, and emtricitabine) in pregnant women compared with the PK in nonpregnant or postpartum (PP) women. Physiological data related to changes in maternal body weight, tissue volume, cardiac output, renal function, blood flows, and cytochrome P450 activity were collected from the literature and incorporated into the structural PBPK model that describes HV or PP women PK data. Subsequently, the changes in exposure (area under the curve (AUC) and maximum concentration (C max)) in pregnant women were simulated. Model-simulated PK profiles were overall in agreement with observed data. The prediction fold error for C max and AUC ratio (pregnant vs. nonpregnant) was less than 1.3-fold, indicating that the pregnant PBPK model is useful. The utilization of this simplified model in drug development may aid in designing clinical studies to identify potential exposure changes in pregnant women a priori for compounds which are mainly eliminated renally or metabolized by CYP3A4.

Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

“…For some drugs, systemic exposure in pregnancy can be predicted based on knowledge of the drug's chemical properties and pharmacokinetics and an understanding of the gestational agedependent changes in maternal physiology and contributions of the fetal-placental unit to alterations in drug distribution (34,35). These predictions can then be tested clinically.…”

Development of a Whole-Body Physiologically Based Pharmacokinetic Approach to Assess the Pharmacokinetics of Drugs in Elderly Individuals

“…Moreover, the value of successful PBPK modelling approaches in children [10, 11], pregnant women [12, 13] and diseased subjects [14, 15], in order to investigate and translate knowledge to special populations, has been recognized by regulatory authorities [16, 17]. This would improve pharmacotherapy and increase the safety of medications, thereby reducing costs resulting from adverse events caused by suboptimal medication.…”

Physiologically Based Pharmacokinetic Modeling in Pregnancy: A Systematic Review of Published Models

“…However, this model was not further developed for humans and the idea of PBPK modeling in pregnancy remained dormant until around 2010, when it suddenly sparked major interest. At that time, different PBPK models for pregnant women were developed in MatLab or as part of Simcyp, GastroPlus, and also in the Open Systems Pharmacology (OSP) software suite which includes the software programs PK‐Sim and MoBi (https://github.com/Open-Systems-Pharmacology/Pregnancy-Models). Some of these models were subsequently used as a basis for further model refinement and/or incorporation of information on system‐specific parameters that were not part of the original model, such as changes in the activity of specific CYP enzymes .…”

“… Some of these models were subsequently used as a basis for further model refinement and/or incorporation of information on system‐specific parameters that were not part of the original model, such as changes in the activity of specific CYP enzymes . Furthermore, a variety of semimechanistic or minimal PBPK models for pregnant women can also be found in the literature . An overview of published articles focusing on pregnancy PBPK modeling in pharmaceutical research during recent years is presented in Figure .…”