Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
Randomized trial of trimetrexate (TMTX), leucovorin (LV) and dapsone (DAP) vs trimethoprim/sulfamethoxazole (T/S) for pneumocystis carinii pneumonia (PCP): clinical and pharmacokinetic results (Meeting abstract).
Proc Annu Meet Am Soc Clin Oncol; 15:A863 1996. Unique Identifier : AIDSLINE ICDB/97635863 Stansell JD; Sattler FR; Dube M; Koda RT; Lee WL; Chaterjee DJ; Sharpe E; Capizzi RL; Kurman MR; Univ. of Southern California, Los Angeles, CA
Abstract:
PCP remains one of the most frequent infections among patients with chronic immunosuppression. TMTX, a non-classical antifol does not use the reduced folate (RF) carrier mechanism to enter cells. Since PCP does not have the RF carrier, TMTX is effective in PCP treatment when given with LV due to selective protection of normal tissues. DAP, an inhibitor of dihydropteroate synthetase, also has activity against PCP. Thus DAP/TMTX creates sequential enzyme blockade in PCP. HIV-positive patients with moderate to severe PCP (D[A-a]O2 of 35-55) were randomized 2:1 to receive TMTX/LV/DAP vs T/S in a double-blind trial. Treatment consisted of 21 +/- 3 days of TMTX 45 mg/m2/day, iv; LV 20 mg/m2 q 6 hr iv or po, and DAP 100 mg/day po or T/S, 15 mg/kg/day po. The study endpoints were survival, relapse free survival one month after completion of treatment, D[A-a]O2 and treatment-limiting toxicity at Days 10 and 21 of treatment. Plasma levels of TMTX, DAP, and monoacetyl dapsone (MAD) were determined using HPLC. 13 patients were randomized to TMTX/LV/DAP and 5 to T/S. Patients were well matched for severity of PCP and CD4 count. The change from baseline in D[A-a]O2 at Day 10 was 25.5 torr for the T/S group, and -12.9 torr for the TMTX group (p = 0.16); at Day 21, these values were -22.8 torr and -21.7 torr for the T/S and TMTX groups, respectively (p = 0.91). Adverse drug reactions occurred in 85% of TMTX treated patients vs 80% of T/S treated patients. 10/13 TMTX treated, and 3/5 T/S treated patients were responders at Day 21. No patients completing therapy relapsed within one month. AUCs (ug/hr/ml) for wk 1 and 3 were 17 and 21 for TMTX; 32 and 37 for DAP; and 24 and 24 for MAD. There were no changes in other TMTX DAP, or MAD PK parameters (t1/2, Cl). TMTX/LV/DAP is well tolerated in PCP. Additional studies with this combination are underway.
Keywords: Dapsone/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE Disease-Free Survival Drug Therapy, Combination HIV Infections/COMPLICATIONS Leucovorin/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE Pneumonia, Pneumocystis carinii/COMPLICATIONS/*DRUG THERAPY Recurrence Trimethoprim-Sulfamethoxazole Combination/ADMINISTRATION & DOSAGE/ *THERAPEUTIC USE Trimetrexate/ADMINISTRATION & DOSAGE/*THERAPEUTIC USE ABSTRACT CLINICAL TRIAL PUBLISHED ERRATUM 970330
M9731530
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Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.
