Race/ethnicity and protease inhibitor use influence plasma tenofovir exposure in adults living with HIV-1 in AIDS Clinical Trials Group Study A5202

AIDS Clinical Trials Group Study A5202 Team

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Abstract

AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (k a ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: k a = 2.87 h -1 , CL/F=37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/ h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

Original languageEnglish (US)
Article numbere01638-18
JournalAntimicrobial agents and chemotherapy
DOIs
StatePublished - Apr 1 2019

Fingerprint

Tenofovir
Protease Inhibitors
efavirenz
HIV-1
Acquired Immunodeficiency Syndrome
Clinical Trials
Ritonavir
Structural Models
Creatinine
Therapeutics
Pharmacokinetics
Placebos
Safety

Keywords

  • Pharmacokinetics
  • Population pharmacokinetics
  • Tenofovir

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

@article{694d70a6756b45f7a30d02db5be1974d,
title = "Race/ethnicity and protease inhibitor use influence plasma tenofovir exposure in adults living with HIV-1 in AIDS Clinical Trials Group Study A5202",
abstract = "AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88{\%} of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (k a ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: k a = 2.87 h -1 , CL/F=37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/ h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.",
keywords = "Pharmacokinetics, Population pharmacokinetics, Tenofovir",
author = "{AIDS Clinical Trials Group Study A5202 Team} and Bednasz, {Cindy J.} and Venuto, {Charles S.} and Qing Ma and Daar, {Eric S.} and Sax, {Paul E.} and Fischl, {Margaret A} and Collier, {Ann C.} and Smith, {Kimberly Y.} and Camlin Tierney and Acosta, {Edward P.} and Mager, {Donald E.} and Morse, {Gene D.}",
year = "2019",
month = "4",
day = "1",
doi = "10.1128/AAC.01638-18",
language = "English (US)",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",

}

TY - JOUR

T1 - Race/ethnicity and protease inhibitor use influence plasma tenofovir exposure in adults living with HIV-1 in AIDS Clinical Trials Group Study A5202

AU - AIDS Clinical Trials Group Study A5202 Team

AU - Bednasz, Cindy J.

AU - Venuto, Charles S.

AU - Ma, Qing

AU - Daar, Eric S.

AU - Sax, Paul E.

AU - Fischl, Margaret A

AU - Collier, Ann C.

AU - Smith, Kimberly Y.

AU - Tierney, Camlin

AU - Acosta, Edward P.

AU - Mager, Donald E.

AU - Morse, Gene D.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (k a ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: k a = 2.87 h -1 , CL/F=37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/ h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

AB - AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (k a ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: k a = 2.87 h -1 , CL/F=37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/ h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.

KW - Pharmacokinetics

KW - Population pharmacokinetics

KW - Tenofovir

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U2 - 10.1128/AAC.01638-18

DO - 10.1128/AAC.01638-18

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JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

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