Methotrexate Decreases Tenofovir Exposure in Antiretroviral-suppressed Individuals Living With HIV

David Gingrich, BS; Amelia N. Deitchman, PharmD, PhD; Amy Kantor, MS; Liusheng Huang, PhD; James H. Stein, MD; Judith S. Currier, MD; Priscilla Y. Hsue, MD; Heather J. Ribaudo, PhD; Francesca T. Aweeka, PharmD

Disclosures

J Acquir Immune Defic Syndr. 2020;85(5):651-658. 

In This Article

Abstract and Introduction

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.

Introduction

A recent study of the AIDS Clinical Trials Group (ACTG), A5314, investigated the use of low-dose methotrexate (LDMTX) to reduce inflammation and also improve endothelial function associated with chronic HIV infection.[1] This study, a phase II trial, investigated the safety and efficacy of LDMTX in participants with adequately controlled HIV on antiretroviral therapy (ART). In this pharmacokinetic (PK) substudy, we hypothesized that tenofovir (TFV), given as tenofovir disoproxil fumarate (TDF), a common component of ART regimens, may be subject to drug–drug interactions with methotrexate (MTX) given that both drugs are renal organic ion transporter (OAT) 1 and OAT3 substrates.

MTX is primarily eliminated renally unchanged via filtration and active secretion via OAT1 and OAT3[2,3] but exhibits other complex pharmacological characteristics, including variable absorption (tmax 0.7–4 hours) and saturable dose-dependent absorption (28%–88% bioavailability).[4–6] It is also significantly metabolized by intestinal flora and intracellularly to more active polyglutamate derivatives retained in the cells until reverse conversion for elimination.[5] Coadministration of OAT-transported substrates, such as penicillins[7,8] and ciprofloxacin[9] have resulted in increased, potentially toxic, MTX levels. MTX has not been identified a perpetrator of renal transport-related drug–drug interactions,[10] but studies are limited.

Similar to MTX, TFV is also eliminated by renal filtration and active secretion by OAT1 and OAT3.[11,12] TFV, administered as TDF, is poorly absorbed (approximately 25% bioavailability).[13] For some known TFV drug interactions, definitive mechanisms are unclear. In the case of higher TFV with protease inhibitors (PIs) (eg, atazanavir[14]), inhibition at the apical membrane resulting in higher TFV accumulation in proximal tubule cells has been proposed. For TFV increasing raltegravir exposure,[15] OAT1 inhibition has been suggested as a potential mechanism.[16]

For MTX, little is known regarding the use of low-dose oral MTX in the context of ART. One study observed no difference in MTX half-life following high-dose intravenous administration to ART-treated people living with HIV (PWH),[17] but did not investigate the impact of MTX on TFV PK.

Such interactions may result in increased TFV or MTX levels, which may result in TFV-mediated renal toxicity via accumulation in renal proximal tubule cells or toxic MTX exposure. Unexpected interactions that may decrease exposure of TFV or MTX, could potentiate loss of viral suppression or loss of MTX anti-inflammatory efficacy, respectively.

We therefore sought to evaluate the potential drug–drug interaction between LDMTX and TFV in PWH. In this A5314 substudy enrolling TFV-treated participants, intensive PK samples were collected and analyzed for TFV and MTX concentrations. Using PK and statistical analyses, we compared TFV exposure between those receiving active MTX to those receiving placebo and characterized low-dose MTX exposure in the context of TFV-containing ART.

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