Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients

Gautam Baheti, Jennifer J. Kiser, Peter L. Havens, Courtney V Fletcher

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h -1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E max), the TFV concentration producing 50% of E max (EC 50), and the intracellular elimination rate constant (k out) of 300 fmol/10 6 cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h -1, respectively. The estimated k out gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

Original languageEnglish (US)
Pages (from-to)5294-5299
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Tenofovir
HIV-1
Pharmacokinetics
Population

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients. / Baheti, Gautam; Kiser, Jennifer J.; Havens, Peter L.; Fletcher, Courtney V.

In: Antimicrobial Agents and Chemotherapy, Vol. 55, No. 11, 01.11.2011, p. 5294-5299.

Research output: Contribution to journalArticle

@article{c5d3752d15944d6895b44135ba69fa59,
title = "Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients",
abstract = "The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h -1; apparent clearance (CL/F), 42 liters/h (33.5{\%} interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8{\%} IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5{\%} IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E max), the TFV concentration producing 50{\%} of E max (EC 50), and the intracellular elimination rate constant (k out) of 300 fmol/10 6 cells (82{\%} IIV), 100 ng/ml (106{\%} IIV), and 0.008 h -1, respectively. The estimated k out gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.",
author = "Gautam Baheti and Kiser, {Jennifer J.} and Havens, {Peter L.} and Fletcher, {Courtney V}",
year = "2011",
month = "11",
day = "1",
doi = "10.1128/AAC.05317-11",
language = "English (US)",
volume = "55",
pages = "5294--5299",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "11",

}

TY - JOUR

T1 - Plasma and intracellular population pharmacokinetic analysis of tenofovir in HIV-1-infected patients

AU - Baheti, Gautam

AU - Kiser, Jennifer J.

AU - Havens, Peter L.

AU - Fletcher, Courtney V

PY - 2011/11/1

Y1 - 2011/11/1

N2 - The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h -1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E max), the TFV concentration producing 50% of E max (EC 50), and the intracellular elimination rate constant (k out) of 300 fmol/10 6 cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h -1, respectively. The estimated k out gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

AB - The relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n = 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h -1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (E max), the TFV concentration producing 50% of E max (EC 50), and the intracellular elimination rate constant (k out) of 300 fmol/10 6 cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h -1, respectively. The estimated k out gave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

UR - http://www.scopus.com/inward/record.url?scp=80054715372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054715372&partnerID=8YFLogxK

U2 - 10.1128/AAC.05317-11

DO - 10.1128/AAC.05317-11

M3 - Article

VL - 55

SP - 5294

EP - 5299

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 11

ER -