Dapsone-Induced Methemoglobinemia A Dose-Related Occurrence?

作者：E**enshade Adam J^*; Ho Richard H; Shintani Ayumi; Zhao Zhiguo; Smith Lesley Ann; Friedman Debra L

来源：Cancer, 2011, 117(15): 3485-3492.

DOI：10.1002/cncr.25904

• pediatric oncology
• human immunodeficiency virus
• dapsone
• methemoglobinemia
• drug-related complications
• cytochrome b5 reductase

BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug-related risk factors were evaluated by Cox proportional hazards, and in a cross-sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5-22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing >= 20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [Cl], 0.09-0.78; P = .016), whereas methemoglobinemia risk was increased with dosing >= 20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P < .001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochron-ie b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. Cancer 2011;117: 3485-92.

• 出版日期2011-8-1