David Gingrich1, Amelia N Deitchman1, Amy Kantor2, Liusheng Huang1, James H Stein3, Judith S Currier4, Priscilla Y Hsue5, Heather J Ribaudo2, Francesca T Aweeka1. 1. Drug Research Unit, Department of Clinical Pharmacy University of California, San Francisco, CA. 2. Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA. 3. Department of Medicine, Cardiovascular Medicine Division, University of Wisconsin School of Medicine and Public Health, Madison, WI. 4. Division of Infectious Diseases, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA and. 5. Cardiology Division, Zuckerberg San Francisco General Hospital, School of Medicine, University of California, San Francisco, CA.
Abstract
BACKGROUND: To mitigate increased risk of premature cardiovascular disease in antiretroviral therapy (ART) suppressed adults living with HIV (PWH), low-dose methotrexate (LDMTX) was evaluated in a multicenter randomized placebo controlled clinical trial of 176 PWH taking various ART regimens (ACTG A5314). Given shared methotrexate (MTX) and tenofovir (TFV) pharmacokinetic (PK) pathways, a substudy was conducted to investigate whether LDMTX alters TFV exposure. METHODS: Adults virally suppressed on ART for >24 weeks were randomized to LDMTX or placebo. The first 66 participants taking a tenofovir disoproxil fumarate-containing regimen underwent intensive PK sampling over 24 hours after the second dose of LDMTX 10 mg or placebo. TFV and MTX levels were quantified using validated mass spectrometry methods. TFV PK between LDMTX and placebo groups were compared and MTX PK was characterized. RESULTS: Forty-eight participants completed this substudy (n = 20 on LDMTX and 28 on placebo). Baseline characteristics were balanced except for protease inhibitor (PI)-use (25% in LDMTX and 43% in placebo groups). For TFV, AUC6 (primary endpoint), and AUC24,imputed, Cmax, and Cmin (secondary endpoints) were on average 22%, and 24%, 27%, and 31% less in the LDMTX versus placebo groups, with reductions in secondary endpoints reaching statistical significance. Additional analyses suggested a greater reduction in the absence of PI although not significant. CONCLUSION: Lower TFV AUC24,imputed and Cmax indicates that LDMTX reduces TFV exposure in PWH. However, this change was modest, not warranting a change in TFV dosing at this time. Further studies of TFV PK with LDMTX, especially without PI co-administration, are warranted.
BACKGROUND: To mitigate increased risk of premature cardiovascular disease in antiretroviral therapy (ART) suppressed adults living with HIV (PWH), low-dose methotrexate (LDMTX) was evaluated in a multicenter randomized placebo controlled clinical trial of 176 PWH taking various ART regimens (ACTG A5314). Given shared methotrexate (MTX) and tenofovir (TFV) pharmacokinetic (PK) pathways, a substudy was conducted to investigate whether LDMTX alters TFV exposure. METHODS: Adults virally suppressed on ART for >24 weeks were randomized to LDMTX or placebo. The first 66 participants taking a tenofovir disoproxil fumarate-containing regimen underwent intensive PK sampling over 24 hours after the second dose of LDMTX 10 mg or placebo. TFV and MTX levels were quantified using validated mass spectrometry methods. TFV PK between LDMTX and placebo groups were compared and MTX PK was characterized. RESULTS: Forty-eight participants completed this substudy (n = 20 on LDMTX and 28 on placebo). Baseline characteristics were balanced except for protease inhibitor (PI)-use (25% in LDMTX and 43% in placebo groups). For TFV, AUC6 (primary endpoint), and AUC24,imputed, Cmax, and Cmin (secondary endpoints) were on average 22%, and 24%, 27%, and 31% less in the LDMTX versus placebo groups, with reductions in secondary endpoints reaching statistical significance. Additional analyses suggested a greater reduction in the absence of PI although not significant. CONCLUSION: Lower TFV AUC24,imputed and Cmax indicates that LDMTX reduces TFV exposure in PWH. However, this change was modest, not warranting a change in TFV dosing at this time. Further studies of TFV PK with LDMTX, especially without PI co-administration, are warranted.
Authors: Dirk R de Waart; Koen van de Wetering; Cindy Kunne; Suzanne Duijst; Coen C Paulusma; Ronald P J Oude Elferink Journal: Drug Metab Dispos Date: 2011-12-13 Impact factor: 3.922
Authors: Priscilla Y Hsue; Heather J Ribaudo; Steven G Deeks; Tanvir Bell; Paul M Ridker; Carl Fichtenbaum; Eric S Daar; Diane Havlir; Eunice Yeh; Ahmed Tawakol; Michael Lederman; Judith S Currier; James H Stein Journal: Clin Infect Dis Date: 2019-05-17 Impact factor: 9.079
Authors: Sudeep P Pushpakom; Neill J Liptrott; Sonia Rodríguez-Nóvoa; Pablo Labarga; Vincent Soriano; Marta Albalater; Elizabeth Hopper-Borge; Stefano Bonora; Giovanni Di Perri; David J Back; Saye Khoo; Munir Pirmohamed; Andrew Owen Journal: J Infect Dis Date: 2011-07-01 Impact factor: 5.226