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

Results

Participant Demographics

Of the 66 participants enrolled in the substudy, 18 were excluded from PK analysis because of missed doses of TFV or failure to meet protocol criteria for dose-escalation to 10 mg of MTX at the time of the substudy. Forty-eight participants completed PK sampling (n = 20 on LDMTX, n = 28 on placebo; a subset of participants were sampled through 24 hours: n = 7 on LDMTX and n = 10 on placebo); all were taking TFV in the form of TDF. Participants were 92% men, 48% white and 46% black; characteristics were balanced across treatment arms with the exception of concomitant PI-use (25% LDMTX, 43% placebo). Complete demographic information for evaluable participants in PK substudy is presented in Table 1.

PK Results

Effect of MTX on TFV PK Parameters. Table 2 details the descriptive statistics of TFV PK parameters by treatment group. The GM (90% CI) for the primary endpoint, TFV AUC6, was 967 (802, 1166) ng·h/mL for the LDMTX group and 1239 (1105, 1390) ng·h/mL for placebo [GM ratio (GMR) = 0.78, 90% CI: (0.64 to 0.96), P = 0.06]. Similar results were observed for AUC24 [GMR = 0.64, 90% CI: (0.45 to 0.91), P = 0.08] and AUC24i [GMR = 0.76, 90% CI: (0.61 to 0.93), P = 0.033]. In addition, mean Cmax was lower in the LDMTX group versus the placebo group [GM =231 ng/mL versus 315 ng/mL, GMR = 0.73, 90% CI: (0.60 to 0.90), P= 0.027]. Trough TFV concentrations (Cmin) did not differ between arms [GMR = 0.69, 90% CI: (0.34 to 1.40), P = 0.39]. Figure 1 depicts the average concentration time profile of TFV with and without MTX co-administration.

Figure 1.

GM plasma concentration–time profile of TFV. Blue (black in print) solid line, TFV with LDMTX; Red (gray in print) dash line, TFV with placebo. Error bars indicate standard error.

Because of the interaction between TFV and PIs and the observed treatment group imbalance, a subgroup analysis by concomitant PI use was performed. This analysis suggested lower TFV concentrations in the presence of LDMTX compared with placebo when taken in conjunction with a non–PI-based regimen; this difference was not apparent in the context of co-administration with a PI regimen (Figure 2). Specifically, a greater effect of MTX on TFV exposure was observed for participants who were not on PIs (non-PI) for LDMTX compared with placebo [Cmax GMRnonPI = 0.7, 90% CI: (0.53 to 0.93), P = 0.045; AUC6 GMRnonPI =0.76, 90% CI: (0.58 to 0.98), P = 0.08; AUC24i GMRnonPI = 0.75, 90% CI: (0.58 to 0.98), P = 0.08]. Although a formal interaction test was not statistically significant (P > 0.3), this test is underpowered given the small study sample.

Figure 2.

GM plasma concentration–time profile of TFV in the context of LDMTX. Blue (black in print) solid line, TFV with LDMTX; Red (gray in print) dash line, TFV with placebo. Error bars indicate standard error.

MTX PK in the Context of TFV-Containing ART

MTX was characterized in the context of TFV. MTX AUC6 was estimated to be 492 (434, 558) ng·h/mL, and Cmax was 144 (127, 164) ng/mL. The GM concentration–time profiles for MTX in the presence of TFV are shown in Figure 1, Supplemental Digital Content, http://links.lww.com/QAI/B557. MTX exposure did not seem to differ by PI use on visual evaluation.

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