title: Semiphysiological versus empirical modelling of the population pharmacokinetics of free and total cefazolin during pregnancy.
abstract: This work describes a first population pharmacokinetic (PK) model for free and total cefazolin during pregnancy, which can be used for dose regimen optimization. Secondly, analysis of PK studies in pregnant patients is challenging due to study design limitations. We therefore developed a semiphysiological modeling approach, which leveraged gestation-induced changes in creatinine clearance (CrCL) into a population PK model. This model was then compared to the conventional empirical covariate model. First, a base two-compartmental PK model with a linear protein binding was developed. The empirical covariate model for gestational changes consisted of a linear relationship between CL and gestational age. The semiphysiological model was based on the base population PK model and a separately developed mixed-effect model for gestation-induced change in CrCL. Estimates for baseline clearance (CL) were 0.119 L/min (RSE 58%) and 0.142 L/min (RSE 44%) for the empirical and semiphysiological models, respectively. Both models described the available PK data comparably well. However, as the semiphysiological model was based on prior knowledge of gestation-induced changes in renal function, this model may have improved predictive performance. This work demonstrates how a hybrid semiphysiological population PK approach may be of relevance in order to derive more informative inferences.
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, P.O. Box 1066 CX, Amsterdam, The Netherlands ; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, P.O. Box 90440, 1006 BK Amsterdam, The Netherlands.
authors.forename: J G Coen
authors.initials: JG
authors.lastname: van Hasselt
authors.affiliation: Department of Development and Regeneration, KU Leuven, Herestraat 49, 300 Leuven, Belgium ; Neonatal Intensive Care Unit, University Hospitals Leuven, Herestraat 49, 300 Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.affiliation: Department of Development and Regeneration, KU Leuven, Herestraat 49, 300 Leuven, Belgium ; Obstetrics and Gynecology, University Hospitals Leuven, Herestraat 49, 300 Leuven, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: van Calsteren
authors.affiliation: Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, P.O. Box 90440, 1006 BK Amsterdam, The Netherlands ; Division of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80125, 3508 TC Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, P.O. Box 1066 CX, Amsterdam, The Netherlands ; Division of Pharmacoepidemiology & Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, P.O. Box 80125, 3508 TC Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Clinical Pharmacology, Netherlands Cancer Institute, Plesmanlaan 121, P.O. Box 1066 CX, Amsterdam, The Netherlands ; Department of Pharmacy & Pharmacology, Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, P.O. Box 90440, 1006 BK Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000328:Adult; D002437:Cefazolin / Q000493:pharmacokinetics*; D003404:Creatinine / Q000378:metabolism; D003710:Demography; D036262:Empirical Research; D005260:Female; D006801:Humans; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011247:Pregnancy; D013997:Time Factors; D055815:Young Adult
chemical_list: D003404:Creatinine; D002437:Cefazolin