J. A. Simpson1,2, R. Price1,3, F. ter Kuile3,4, P. Teja-Isavatharm5, F. Nosten1,2,3, T. Chongsuphajaisiddhi2, S. Looareesuwan2, L. Aarons5, N. J. White1,2
1) Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford, UK. 2) Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 3) Shoklo Malaria Research Unit, Mae Sod, Tak Province, Thailand. 4) Division of Infectious Diseases, University of Amsterdam, Amsterdam, Netherlands. 5) Department of Immunology and Medicine, AFRIMS, Bangkok, Thailand. 6) School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK.
Mefloquine is the treatment of choice for multi-drug resistant falciparum malaria. The factors which influence the pharmacokinetic properties of mefloquine in acute malaria are not well characterised. Population methods of pharmacokinetic analysis (ie, performing mixed-effects modelling) provide a means of identifying and quantifying the factors that contribute to variance in pharmacokinetic measures (both interindividual and intraindividual factors).
The pharmacokinetic properties of mefloquine were evaluated in 257 patients with acute falciparum malaria using non-linear mixed effect modelling (Lindstrom & Bates, 1990). Two different oral dosage regimens were used; a split dose of 15 mg base /kg initially followed by 10 mg/kg 24 hours later (n=159), and a single dose of 25 mg/kg (n=98). Mefloquine was combined with artesunate in 105 (41%) patients (74 received a split dose and 31 a single dose).
Splitting the mefloquine dose increased the AUC0-¥ by 50% (95% CI: 36%, 65%) for monotherapy and by 20% (95% CI: 3%, 40%) for combined therapy. The apparent volume of distribution (V/F) was significantly lower in patients receiving split doses of mefloquine monotherapy (mean [95% CI]: 8.14 [7.49,8.86] l/kg) compared to a single dose (20.37 [16.26, 25.51] l/kg). Patients who received mefloquine monotherapy and cleared parasitemia in less than 48 hours had a significantly higher AUC0-¥ independent of any confounders, compared to patients with slower parasite clearance (geometric mean [95% CI]: 50373 [46121, 55017] vs 45583 [42306, 49125] ng/ml*day).
The pharmacokinetic properties of mefloquine in malaria were relatively unaffected by demographic variables, other than body weight, or disease severity. Assuming apparent clearance and volume of distribution are unaffected by dose regimen then splitting the 25 mg/kg mefloquine dosage improves oral bioavailability and the therapeutic response in the treatment of acute falciparum malaria.
Lindstrom, M.J. & Bates, D.M. (1990) Nonlinear mixed effects models for repeated measures data. Biometrics, 46, 673-687.
Reference: PAGE 9 (2000) Abstr 100 [www.page-meeting.org/?abstract=100]
Poster: poster