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Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women

The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN‐001 clinical trial, an...

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Autores principales: Burns, Rebecca N., Hendrix, Craig W., Chaturvedula, Ayyappa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008110/
https://www.ncbi.nlm.nih.gov/pubmed/25581815
http://dx.doi.org/10.1002/jcph.461
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author Burns, Rebecca N.
Hendrix, Craig W.
Chaturvedula, Ayyappa
author_facet Burns, Rebecca N.
Hendrix, Craig W.
Chaturvedula, Ayyappa
author_sort Burns, Rebecca N.
collection PubMed
description The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN‐001 clinical trial, an open label 3‐way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2‐compartment, first‐order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV‐DP by first‐order uptake with first‐order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (V(c)) with estimates as follows: absorption rate constant (Ka) 9.79 h(−1), absorption lag time 0.5 hours, V(c) 385.71–2.16*(73‐WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)*V(c)). TFV‐DP's half‐life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN‐001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV‐DP when compared to healthy participant data from another clinical trial.
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spelling pubmed-50081102016-09-16 Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women Burns, Rebecca N. Hendrix, Craig W. Chaturvedula, Ayyappa J Clin Pharmacol Pharmacometrics The objective of this analysis was to develop and qualify a population pharmacokinetic model describing plasma tenofovir (TFV) concentrations and tenofovir‐diphosphate (TFV‐DP) concentrations in peripheral blood mononuclear cell (PBMC) in healthy women volunteers from the MTN‐001 clinical trial, an open label 3‐way crossover study of oral tenofovir disoproxil fumarate 300 mg tablet, TFV 1% vaginal gel, or both. TFV pharmacokinetics were best described by a 2‐compartment, first‐order absorption/elimination model with absorption lag time. TFV was linked to PBMC TFV‐DP by first‐order uptake with first‐order elimination. An adherence adjustment was included to account for nonadherence by explicitly modeling a bioavailability parameter on the previous day's dose. The final model included weight as a covariate on central compartment volume (V(c)) with estimates as follows: absorption rate constant (Ka) 9.79 h(−1), absorption lag time 0.5 hours, V(c) 385.71–2.16*(73‐WT(kg)), and apparent TFV clearance of 56.7 L/h ((K20 + K24)*V(c)). TFV‐DP's half‐life was 53.3 hours. All diagnostic plots and bootstrap confidence intervals were acceptable. Model validation was conducted using simulations compared to data from the MTN‐001 oral + vaginal period and other clinical trial data. The resulting model closely predicted the disposition of TFV and TFV‐DP when compared to healthy participant data from another clinical trial. John Wiley and Sons Inc. 2015-02-04 2015-06 /pmc/articles/PMC5008110/ /pubmed/25581815 http://dx.doi.org/10.1002/jcph.461 Text en © 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Pharmacometrics
Burns, Rebecca N.
Hendrix, Craig W.
Chaturvedula, Ayyappa
Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
title Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
title_full Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
title_fullStr Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
title_full_unstemmed Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
title_short Population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
title_sort population pharmacokinetics of tenofovir and tenofovir‐diphosphate in healthy women
topic Pharmacometrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008110/
https://www.ncbi.nlm.nih.gov/pubmed/25581815
http://dx.doi.org/10.1002/jcph.461
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