title: 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.
authors.affiliation: Novartis Institutes for Biomedical Research, DMPK-Translational Sciences, One Health Plaza 436/3253, East Hanover, New Jersey, 07470, USA.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Xia
authors.forename: Tycho
authors.initials: T
authors.lastname: Heimbach
authors.forename: Rakesh
authors.initials: R
authors.lastname: Gollen
authors.forename: Charvi
authors.initials: C
authors.lastname: Nanavati
authors.forename: Handan
authors.initials: H
authors.lastname: He
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D005544:Forecasting; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism / Q000652:urine*; D011247:Pregnancy / Q000187:drug effects / Q000652:urine*; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology
chemical_list: D004364:Pharmaceutical Preparations; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A