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 (ka), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 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 language | English (US) |
---|---|
Article number | e01638-18 |
Journal | Antimicrobial agents and chemotherapy |
Volume | 63 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2019 |
Keywords
- Pharmacokinetics
- Population pharmacokinetics
- Tenofovir
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)
- Infectious Diseases
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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.
In: Antimicrobial agents and chemotherapy, Vol. 63, No. 4, e01638-18, 04.2019.Research output: Contribution to journal › Article › peer-review
}
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.
N1 - Funding Information: E.S.D.’s institution receives grant support from Gilead, Merck, and ViiV, and E.S.D. is a consultant for Bristol Myers Squibb, Gilead, Merck, Janssen, Teva, and ViiV. A.C.C. is a member of a Data and Safety Monitoring Board for a Merck-sponsored study, and her institution has received grant support from Bristol-Myers-Squibb. K.Y.S. is an employee of ViiV Healthcare, beginning December 2013. All other authors have no conflict of interest to declare. Funding Information: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, UM1 AI069424, UM1 AI069511, and UM1 AI106701. Research was supported in part by the University of Rochester Center for AIDS Research under award number P30 AI078498, the University of Washington/Fred Hutchinson Cancer Research Center for AIDS Research under award number UM1 AI27757, the University of California San Francisco Pharmacology Core under award number P30 AI022763, the University of North Carolina Center for AIDS Research under award number P30 AI050410, and the University at Buffalo Pharmacology Specialty Laboratory and the University of Alabama Pharmacology Specialty Laboratory under award number UM1 AI106701. C. S. Venuto and Q. Ma were supported in part by grants K23AI108355 and K08MH098794, respectively. Funding Information: We thank the study participants for their generous donation of time and effort in the successful completion of clinical trial A5202. We also thank Olivia Campagne (University at Buffalo, SUNY) for advice on population modeling and Katie Mollan (University of North Carolina, UNC) for advice and statistical contributions to ACTG A5202. We also acknowledge contributions, either financial and/or drug related, made by GSK/ViiV Healthcare, Gilead, Bristol-Myers Squibb, and Abbott (AbbVie) to the parent study (A5202) and/or substudies of A5202. Other investigators and contributors included the following: Hector H. Bolivar and Sandra Navarro, University of Miami (site 901), CTU grant AI069477, ACTG grant AI27675, and CFAR grant AI073961; Susan L. Koletar and Diane Gochnour, Ohio State University (site 2301), CTU grant AI069474; Edward Seefried and Julie Hoffman, University of California, San Diego (site 701), CTU grant AI69432; Judith Feinberg and Michelle Saemann, University of Cincinnati (site 2401), CTU grant AI069513; Kristine Patterson, Donna Pittard, and David Currin, University of North Carolina (site 3201), CTU grant AI69423, CFAR grant AI50410, GCRC grant RR00046, and grant RR025747; Kerry Upton and Michael Saag, University of Alabama (site 5801), CTU grant U01 AI069452, CCTS grant 1UL1 RR025777-01; Graham Ray and Steven Johnson, University of Colorado Health Sciences Center (site 6101), CTU grant AI69450, grant AI054907, and grant RR00051; Bartolo Santos and Connie A. Funk, University of Southern California (site 1201), CTU grant 5U01 AI069428; Michael Morgan and Brenda Jackson, Vanderbilt Therapeutics CRS (site 3652), CTU grant AI069439; Pablo Tebas and Aleshia Thomas, University of Pennsylvania, subunit of Children's Hospital of Philadelphia (site 6201), CTU grant U01 AI069467-03, CFAR grant 5P30 AI045008-10; Ge-Youl Kim and Michael K. Klebert, Washington University (site 2101), CTU grant AI069495; Jorge L. Santana and Santiago Marrero, University of Puerto Rico (site 5401), CTU grant 5U01 AI069415-03; Jane Norris and Sandra Valle, Stanford University (site 501), CTU grant AI69556; Gary Matthew Cox and Martha Silberman, Duke University Medical Center (site 1601), CTU grant 5U01 AI069484-02; Sadia Shaik and Ruben Lopez, Harbor-University of California, Los Angeles Medical Center (site 603), CTU grant AI069424; Margie Vasquez and Demetre Daskalakis, New York University/NYC HHC at Bellevue Hospital Center (site 401), CTU grant AI069532; Christina Megill and Todd Stroberg, Cornell Chelsea (site 7804), CTU grant AI69419, CSTC grant RR024996; Jessica Shore and Babafemi Taiwo, Northwestern University CRS (site 2701), CTU grant AI069471; Mitchell Goldman and Molly Boston, Indiana University (site 2601), CTU grant UO1 AI025859; Jeffrey Lennox and Carlos del Rio, Ponce de Leon Center (A5802), CTU grant 5U01 AI069418, CFAR grant P30AI050409; Timothy W. Lane and Kim Epperson, Moses H. Cone Memorial Hospital (site 3203), CTU grant 1U01 A1069423-01; Annie Luetkemeyer and Mary Payne, University of California, San Francisco (site 801), CTU grant 1U01 AI069502-01; Barbara Gripshover and Dawn Antosh, Case Western Reserve University (site 2501), CTU grant AI69501; Jane Reid and Mary Adams, University of Rochester (site 1101), CTU grant U01 AI069511, GCRC grant UL1 RR024160; Sheryl S. Storey and Shelia B. Dunaway, University of Washington (site 1401), CTU grant AI069434; Joel Gallant and Ilene Wiggins, Johns Hopkins University (site 201), CTU grant AI69465; Kimberly Y. Smith and Joan A. Swiatek, Rush University Medical Center (site 2702), CTU grant 5U01 AI069471; Joseph Timpone and Princy Kumar, Georgetown University (site 1008), CTU grant 1U01 AI069494-01; Ardis Moe and Maria Palmer, University of California, Los Angeles Care Center (site 601), CTU grant AI069424; Jon Gothing and Joanne Delaney, Brigham and Women's Hospital, Boston, MA (site 107), CTU grant AI069472; Kim Whitely and Ann Marie Anderson, Metro Health Center (site 2503), CTU grant AI069501; Scott M. Hammer and Michael T. Yin, HIV Prevention & Treatment (Columbia University) (site 30329), CTU grant 5U01 AI069470, grant 1UL1 RR024156; Mamta Jain and Tianna Petersen, UT Southwestern Medical Center at Dallas (site 3751), CTU grant 3U01 AI046376 05S4; Roberto Corales and Christine Hurley, AIDS Community Health Center (site 1108), CTU grant U01AI069511, GCRC grant UL1 RR024160; Keith Henry and Bette Bordenave, Hennepin County Medical Center (site 1502), grant N01 AI72626; Amanda Youmans and Mary Albrecht, Beth Israel Deaconess (Partners/Harvard) CRS (site 103), CTU grant UOI A106947203; Richard B. Pollard and Abimbola Olusanya, University of California, Davis Medical Center (site 3851), grant AI38858; Paul R. Skolnik and Betsy Adams, Boston Medical Center CRS (site 104), CTU grant AI069472; Karen T. Tashima and Helen Patterson, Miriam Hospital- Brown University (Partners/Harvard) (site 2951), CTU grant 1U01 AI069472-01; Michelle Ukwu and Lauren Rogers, Peabody Health Center (site 31443), CTU grant AI069471; Henry H. Balfour, Jr., and Kathy A. Fox, University of Minnesota (site 1501), CTU grant AI27661; Susan Swindells and Frances Van Meter, University of Nebraska Medical Center (site 1505), CTU grant AI27661; University of Hawaii (site 5201), CTU grant AI34853; Gregory Robbins and Nicole Burgett-Yandow, Massachusetts General Hospital from the Partners/Harvard/BMC ACTU (site 101), CTU grant 1U01 AI069472-01; Charles E. Davis, Jr., and Colleen Boyce, IHV Baltimore Treatment CRS (site 4651), CTU grant 5U01 AI069447 03; William A. O'Brien and Gerianne Casey, University of Texas Medical Branch (site 6301), CTU grant AI032782; Gene D. Morse and Chiu-Bin Hsaio, SUNY-Buffalo (site 1102), CTU grant 5U01 A1027658; San Mateo County AIDS Program (site 505), CTU grant AI27666; Jeffrey L. Meier and Jack T. Stapleton, University of Iowa Healthcare (site 1504), NIAID grant AI27661, grant AI58740; Donna Mildvan and Manuel Revuelta, Beth Israel Medical Center ACTU (site 2851), CTU grant AI46370; David Currin, Wake County HHS (site 30076), CTU grant AI25868; Wafaa El Sadr and Avelino Loquere, Harlem ACTG CRS (site 31483), CTU grant 5U01 AI069470-03; Nyef El-Daher and Tina Johnson, McCree McCuller Wellness Center (site 1107), CTU grant U01 AI069511, GCRC grant UL1 RR024160; Robert Gross and Kathyrn Maffei, University of Pennsylvania Health (site 6206), CTU grant 1U01 AI69467-01; Valery Hughes and Glenn Sturge, Cornell Uptown (site 7803), CTU grant 1U01 AI069419-01; Deborah McMahon and Barbara Rutecki, University of Pittsburgh (site 1001), CTU grant 1UO1 AI069494-01; Michael Wulfsohn, Andrew Cheng, and Norbert Bischofberger, Gilead Sciences; and Lynn Dix and Qiming Liao, GlaxoSmithKline, Inc. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers UM1 AI068634, UM1 AI068636, UM1 AI069424, UM1 AI069511, and UM1 AI106701. Research was supported in part by the University of Rochester Center for AIDS Research under award number P30 AI078498, the University of Washington/Fred Hutchinson Cancer Research Center for AIDS Research under award number UM1 AI27757, the University of California San Francisco Pharmacology Core under award number P30 AI022763, the University of North Carolina Center for AIDS Research under award number P30 AI050410, and the University at Buffalo Pharmacology Specialty Laboratory and the University of Alabama Pharmacology Specialty Laboratory under award number UM1 AI106701. C. S. Venuto and Q. Ma were supported in part by grants K23AI108355 and K08MH098794, respectively. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. E.S.D.'s institution receives grant support from Gilead, Merck, and ViiV, and E.S.D. is a consultant for Bristol Myers Squibb, Gilead, Merck, Janssen, Teva, and ViiV. A.C.C. is a member of a Data and Safety Monitoring Board for a Merck-sponsored study, and her institution has received grant support from Bristol-Myers-Squibb. K.Y.S. is an employee of ViiV Healthcare, beginning December 2013. All other authors have no conflict of interest to declare. Publisher Copyright: Copyright © 2019 American Society for Microbiology. All Rights Reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/4
Y1 - 2019/4
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 (ka), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 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 (ka), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 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
UR - http://www.scopus.com/inward/record.url?scp=85063948365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063948365&partnerID=8YFLogxK
U2 - 10.1128/AAC.01638-18
DO - 10.1128/AAC.01638-18
M3 - Article
C2 - 30642925
AN - SCOPUS:85063948365
VL - 63
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 4
M1 - e01638-18
ER -