title: Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy.
abstract: Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis-Menten constant (K m) and the maximum rate of metabolite formation (V max) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration-time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41%, respectively, which were in line with the observed decreases of 17-22 and 33%. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.
authors.affiliation: Department of Pharmacy, Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Colbers
authors.affiliation: Department of Pharmacology and Toxicology (149), Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. rick.greupink@radboudumc.nl.
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.affiliation: Department of Pharmacy, Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.|Department of Pharmacology and Toxicology (149), Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Carlijn
authors.initials: C
authors.lastname: Litjens
authors.affiliation: Department of Pharmacy, Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.affiliation: Department of Pharmacology and Toxicology (149), Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000328:Adult; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D000069454:Darunavir / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008954:Models, Biological; D011247:Pregnancy / Q000378:metabolism*; D019438:Ritonavir / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D019438:Ritonavir; D000069454:Darunavir