Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism

K. Madrasi, R. N. Burns, C. W. Hendrix, M. J. Fossler, Ayyappa Chaturvedula

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV-DP median Cmax from the model was 38.5 fmol/106 cells, which is bracketed by two reported healthy volunteer studies (38 and 51 fmol/106 cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV.

Original languageEnglish
Article numbere147
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume3
Issue number11
DOIs
StatePublished - 1 Jan 2014

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Tenofovir
Pharmacokinetics
Phosphorylation
Metabolites
Metabolism
Linking
Cell
Kinetics
Enzyme kinetics
Population
Enzyme Kinetics
Mass Transport
Empirical Model
Blood
Drugs
Model
Model-based
Mass transfer

Cite this

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abstract = "Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV-DP median Cmax from the model was 38.5 fmol/106 cells, which is bracketed by two reported healthy volunteer studies (38 and 51 fmol/106 cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV.",
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Linking the population pharmacokinetics of tenofovir and its metabolites with its cellular uptake and metabolism. / Madrasi, K.; Burns, R. N.; Hendrix, C. W.; Fossler, M. J.; Chaturvedula, Ayyappa.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 3, No. 11, e147, 01.01.2014.

Research output: Contribution to journalArticle

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AU - Madrasi, K.

AU - Burns, R. N.

AU - Hendrix, C. W.

AU - Fossler, M. J.

AU - Chaturvedula, Ayyappa

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AB - Empirical pharmacokinetic models are used to explain the pharmacokinetics of the antiviral drug tenofovir (TFV) and its metabolite TFV diphosphate (TFV-DP) in peripheral blood mononuclear cells. These empirical models lack the ability to explain differences between the disposition of TFV-DP in HIV-infected patients vs. healthy individuals. Such differences may lie in the mechanisms of TFV transport and phosphorylation. Therefore, we developed an exploratory model based on mechanistic mass transport principles and enzyme kinetics to examine the uptake and phosphorylation kinetics of TFV. TFV-DP median Cmax from the model was 38.5 fmol/106 cells, which is bracketed by two reported healthy volunteer studies (38 and 51 fmol/106 cells). The model presented provides a foundation for exploration of TFV uptake and phosphorylation kinetics for various routes of TFV administration and can be updated as more is known on actual mechanisms of cellular transport of TFV.

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