The pharmacokinetics of high-dose methotrexate in people living with HIV on antiretroviral therapy

Abstract

Purpose: Clinical outcomes for lymphoma in people living with HIV (PLWH) are similar to those in the general public. However, a number of concerns remain including pharmacological interactions between cytotoxic chemotherapy and antiretroviral therapy (ARVs). Much attention has focussed on pharmacokinetic interactions attributable to effects on hepatic microsomal enzymes, but not on competition for the renal organic anion transport system. High-dose (3 g/m2) intravenous methotrexate (MTX) is part a of (R)-CODOX-M/IVAC chemotherapy regimen for HIV-associated Burkitt/Burkitt-like lymphoma (BL/BLL). We investigated MTX pharmacokinetics and evaluated the effects of renal function (EGFR), age and use of different classes of ARVs. Methods: Forty-three PLWH treated with ARVs and (R)-CODOX-M/IVAC are included in the analysis. Plasma MTX concentration was measured (ARK TM MTX assay, VITROS® 5600) daily after administration until levels were <0.04/mmol/L. MTX elimination half-life was correlated with age, renal function and antiretroviral regimen. Results: One hundred and fifty timed plasma MTX levels were collected. The median MTX elimination half-life was 21.7 h (range 9.4-204.4). MTX elimination half-life was not influenced by age (p = 0.71), EGFR (p = 0.67) or use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) or integrase inhibitors (p = 0.15). Similarly, different NRTI backbones did not affect MTX elimination kinetics (p = 0.68), despite the potential overlapping competition for active renal tubular transporters between MTX and tenofovir. Conclusion: Although there is potential competition for active renal tubular transporters between MTX and tenofovir, no prolongation of MTX half-life was observed. These findings are reassuring to clinicians managing patients with dual diagnoses.