Population pharmacokinetics of mefloquine in patients with acute falciparum malaria

Objective: To construct a population pharmacokinetic model for mefloquine i n the treatment of falciparum malaria. Background: Mefloquine is the treatment of choice for multidrug-resistant f alciparum malaria. The factors that influence the pharmacokinetic propertie s of mefloquine in acute malaria are not well characterized, Methods: The pharmacokinetic properties of mefloquine were evaluated in 257 patients with acute falciparum malaria by use of nonlinear mixed-effects m odeling. Two different oral dose regimens were used: (1) a split dose of 15 mg base/kg initially followed by 10 mg/kg 24 hours later (n = 159) and (2) a single dose of 25 mg/kg (n = 98), Mefloquine was combined with artesunat e in 105 (41%) patients (74 received a split dose and 31 received a single dose). Results: Splitting the mefloquine dose increased the area under the concent ration-time curve [AUC(0-infinity)] by 50% (95% confidence interval [CI], 3 6% to 65%) for monotherapy and by 20% (95% CI, 3% to 40%) for combined ther apy. The apparent volume of distribution (V/F) was significantly lower in p atients receiving split doses of mefloquine monotherapy (mean, 8.14 L/kg; 9 5% CI, 7.49 to 8.86 L/kg) compared with a single dose (mean, 20.37 L/kg; 95 % CI, 16.26 to 25.51 L/kg), Patients who received mefloquine monotherapy an d cleared parasitemia in less than 48 hours had a significantly higher AUC( 0-infinity) independent of any confounders, compared with patients with slo wer parasite clearance (geometric mean [95% CI], 50,373 ng/mL.day [46,121 t o 55,017 ng/mL.day] versus 45,583 ng/mL.day [42,306 to 49,125 ng/mL.day]), Conclusions: The pharmacokinetic properties of mefloquine in malaria were r elatively unaffected by demographic variables (other than body weight) or d isease severity. Lf it is assumed that apparent clearance and volume of dis tribution are unaffected by dose regimen, then splitting the 25 mg/kg meflo quine dose improves oral bioavailability and the therapeutic response in th e treatment of acute falciparum malaria.