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Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy

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 pot...

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Autores principales: Colbers, Angela, Greupink, Rick, Litjens, Carlijn, Burger, David, Russel, Frans G. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761019/
https://www.ncbi.nlm.nih.gov/pubmed/26369773
http://dx.doi.org/10.1007/s40262-015-0325-8
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author Colbers, Angela
Greupink, Rick
Litjens, Carlijn
Burger, David
Russel, Frans G. M.
author_facet Colbers, Angela
Greupink, Rick
Litjens, Carlijn
Burger, David
Russel, Frans G. M.
author_sort Colbers, Angela
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-015-0325-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-47610192016-03-01 Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy Colbers, Angela Greupink, Rick Litjens, Carlijn Burger, David Russel, Frans G. M. Clin Pharmacokinet Original Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-015-0325-8) contains supplementary material, which is available to authorized users. Springer International Publishing 2015-09-14 2016 /pmc/articles/PMC4761019/ /pubmed/26369773 http://dx.doi.org/10.1007/s40262-015-0325-8 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Colbers, Angela
Greupink, Rick
Litjens, Carlijn
Burger, David
Russel, Frans G. M.
Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy
title Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy
title_full Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy
title_fullStr Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy
title_full_unstemmed Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy
title_short Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy
title_sort physiologically based modelling of darunavir/ritonavir pharmacokinetics during pregnancy
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761019/
https://www.ncbi.nlm.nih.gov/pubmed/26369773
http://dx.doi.org/10.1007/s40262-015-0325-8
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