title: The pharmacokinetics of high-dose methotrexate in people living with HIV on antiretroviral therapy.
abstract: OBJECTIVE
  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/m(2)) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
authors.forename: Alessia
authors.initials: A
authors.lastname: Dalla Pria
authors.affiliation: Department of Oncology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
authors.forename: Maggie
authors.initials: M
authors.lastname: Bendle
authors.affiliation: Department of Oncology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK.
authors.forename: Ramya
authors.initials: R
authors.lastname: Ramaswami
authors.affiliation: Department of HIV Medicine, Chelsea and Westminster Hospital, London, SW10 9NH, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.affiliation: Department of Oncology, Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH, UK. m.bower@imperial.ac.uk.
authors.forename: Mark
authors.initials: M
authors.lastname: Bower
mesh_terms: D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000209:etiology; D003520:Cyclophosphamide / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000627:therapeutic use; D004347:Drug Interactions; D005047:Etoposide / Q000627:therapeutic use; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy; D006207:Half-Life; D006801:Humans; D007069:Ifosfamide / Q000627:therapeutic use; D007677:Kidney Function Tests; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008875:Middle Aged; D012189:Retrospective Studies; D000068698:Tenofovir / Q000494:pharmacology / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D003561:Cytarabine; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D000068698:Tenofovir; D007069:Ifosfamide; D008727:Methotrexate
keywords: Chemotherapy; HIV; Methotrexate; Pharmacokinetics