New fixed dose artesunate/mefloquine for treating multidrug resistant <i>Plasmodium falciparum</i> in adults – a comparative phase IIb safety and pharmacokinetic study with standard dose non-fixed artesunate plus mefloquine.
Olliaro, P., Kiechel, J.R., Navaratnam, V., Ramanathan, S., Vaillant, M., Krudsood, S., Looareesuwan, S., Tangpukdee, N., Wilairatama, P., Phumratanaprapin, W., Leowattana, W., Chalermrut, K., Taylor, W.R.J.
A new fixed-dose artesunate (AS)-mefloquine (MQ) formulation was assessed in adults hospitalized for 28 days in Bangkok, Thailand, with uncomplicated drug-resistant falciparum malaria. The patients (n = 25 per arm) were treated with (i) two fixed-dose tablets (100 mg AS and 200 mg MQ per tablet) daily for 3 days (days 0, 1, and 2) (AS-MQ arm); or (ii) nonfixed AS (4 mg/kg of body weight per day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight (AS-plus-MQ arm). Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P ≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P ≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). The fixed and nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. It is concluded that fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.
Antimicrobial Agents and Chemotherapy (2010) 54 (9) 3730-3737 [doi:10.1128/AAC.01187-09].