Biopharmaceutical Characteristics of Nifurtimox Tablets for Age‐ and Body Weight‐Adjusted Dosing in Patients With Chagas Disease

Treatment of Chagas disease with nifurtimox requires age‐ and body weight‐adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120‐mg tablet and a 30‐mg tablet developed to improve dose accuracy. Two open‐label, randomized crossover studies were conducted in adult outpatients with Chagas disease. One study investigated whether 4 × 30‐mg tablets and 1 × 120‐mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high‐calorie/high‐fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30‐mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least‐squares (LS) mean ratios for both AUC(0‐tlast) and C(max) were in the range of 80%‐125%. The 4 × 30‐mg and 1 × 120‐mg tablet doses were bioequivalent (AUC(0‐tlast): LS mean ratio, 104.7%; 90%CI, 99.1%‐110.7%; C(max): LS mean ratio, 101.7%; 90%CI, 89.4%‐115.6%; n = 24). Exposure when giving the 4 × 30‐mg dose as a slurry or as tablets was comparable, with an AUC(0‐tlast) ratio of 93.2% (84.2%‐103.1%; n = 12) and a slightly decreased C(max) ratio for the slurry of 76.5% (68.8%‐85.1%). Food improved the bioavailability of nifurtimox substantially (AUC(0‐tlast) ratio(fed/fasted), 172%; 90%CI, 154%‐192%; C(max) ratio(fed/fasted), 168%; 90%CI, 150%‐187%). The data indicate that the 30‐ and 120‐mg tablets are suitable for dosing adult and pediatric patients accurately; nifurtimox should be administered under fed conditions.