Prophylactic Trimethoprim-Sulfamethoxazole Does Not Affect Pharmacokinetics or Pharmacodynamics of Methotrexate.
Trimethoprim-sulfamethoxazole (TMP/SMX) is used as prophylaxis against Pneumocystis jiroveci during chemotherapy. Many groups recommend withholding TMP/SMX during high-dose methotrexate (HDMTX) for concerns that it will delay methotrexate clearance. We compared methotrexate exposure following HDMTX (NCT00549848) in 424 patients including 783 courses that were given concurrently and 602 courses that were not given concurrently with TMP/SMX. Among 176 patients (555 courses) on the low-risk arm (HDMTX=2.5 g/m/24 h), there was no difference in clearance (110.7 [1.8%] vs. 108.2 [0.9%] mL/min/m, P=0.3) nor in 42 hour methotrexate concentration (0.37 [5.1%] vs. 0.40 (5.0%) μM, P=0.23). Among 248 patients (830 courses) on the standard/high-risk arm (HDMTX ~5 g/m/24 h), there was slightly higher clearance (95.5 [1.4%] vs. 91.2 [0.8%] mL/min/m, P=0.005) in those receiving TMP/SMX, with no difference in the 42 hour methotrexate concentration (0.59 [4.1%] vs. 0.66 [4.2%] μM, P=0.06). There was no difference in neutrophil counts based on TMP/SMX during HDMTX (P=0.83). TMP/SMX also did not have a significant impact on myelosuppression of low-dose methotrexate (40 mg/m) given during continuation therapy among 230 patients enrolled on a prior study (NCT00137111). Thus, we found no evidence for an interaction between methotrexate and TMP/SMX given prophylactically.
Departments of *Pharmaceutical Sciences §Oncology †Biostatistics, St Jude Children's Research Hospital, Memphis, TN ‡Department of Pediatric Oncology, Skejby Hospital, Aarhus University, Aarhus, Denmark.
Courtney S
CS
Watts
Joseph N
JN
Sciasci
Jennifer L
JL
Pauley
John C
JC
Panetta
Deqing
D
Pei
Cheng
C
Cheng
Caroline M
CM
Christensen
Torben S
TS
Mikkelsen
Ching-Hon
CH
Pui
Sima
S
Jeha
Mary V
MV
Relling
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D004347:Drug Interactions; D006801:Humans; D008727:Methotrexate / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis / Q000517:prevention & control*; D011446:Prospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000627:therapeutic use*
D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D008727:Methotrexate