Population pharmacokinetics of lumefantrine in pregnant women treated with co-artemether for uncomplicated falciparum malaria
R. McGready (1,2,3), J. Tarning (2), N. Lindegardh (2,3), E.A. Ashley (1,2,3), M. Pimanpanarak (1), B. Kamanikom (2), A. Annerberg (2), P. Singhasivanon (2), N.J. White (2,3), F. Nosten (1,2,3)
(1) Shoklo Malaria Research Unit, Mae Sot, Thailand; (2) Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand; (3) Centre for Vaccinology and Tropical Medicine, Churchill Hospital, Oxford, UK.
Objectives: The fixed combination of artemether and lumefantrine (co-artemether) is today the most widely used co-formulated artemisinin-based antimalarial combination therapy manufactured to GMP standards. Pregnancy was recently shown to be associated with reduced plasma concentrations of both artemether and lumefantrine in a detailed pharmacokinetic study of thirteen pregnant women with falciparum malaria . The main objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multi-drug resistant falciparum malaria in Thailand.
Methods: Pregnant women (n=103) with falciparum malaria in the 2nd and 3rd trimester of pregnancy were enrolled to receive artemether-lumefantrine (80-480 mg) BID for three days. All patients provided five finger prick plasma samples for drug quantification, randomly distributed over 14 days. Concentration-time profiles of lumefantrine were modeled with nonlinear mixed-effects population modeling using NONMEM.
Results: Lumefantrine population pharmacokinetics was well described by a two-compartment model with first order absorption and elimination. Absorption lag-time significantly improved the model fit. Several covariates, such as BMI, body-weight, age, estimated gestational age (EGA), influenced the pharmacokinetics when modeled individually. The final model could be reduced to include inter-individual variability on CL/F, Vc/F and Ka with linear covariate relationships between EGA and Vc/F and Q/F. Higher day seven concentrations (mean [range] ng/mL) were observed in this study (483 [134-1454]) compared to non-pregnant adults (350 [204-869]) and previously reported in pregnant patients (384 [62-835]) [1,2]. Mean day seven concentrations were lower but not statistically different in recrudescent patients compared with cured in the present study; 399 (164-551) and 513 (138-1454), respectively.
Conclusions: Day seven concentrations of lumefantrine have been shown to correlate well with total drug exposure and efficacy in large clinical studies . The unusual low cure rate observed in this study can not be explained by lower total drug exposure (day seven concentrations). However, this study uses capillary plasma compared to previous results based on venous sampling. The highly variable pharmacokinetic properties of lumefantrine require further studies to establish a pharmacokinetic-pharmacodynamic relationship in pregnant women.
 McGready R, Stepniewska K, Lindegardh N, Ashley EA, La Y, Singhasivanon P, White NJ, Nosten F. The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria. Eur J Clin Pharmacol. 2006 Dec;62(12):1021-31.
 Ashley EA, Stepniewska K, Lindegårdh N, McGready R, Annerberg A, Hutagalung R, Singtoroj T, Hla G, Brockman A, Proux S, Wilahphaingern J, Singhasivanon P, White NJ, Nosten F. Pharmacokinetic study of artemether-lumefantrine given once daily for the treatment of uncomplicated multidrug-resistant falciparum malaria. Trop Med Int Health. 2007 Feb;12(2):201-8.
 White NJ, van Vugt M, Ezzet F. Clinical pharmacokinetics and pharmacodynamics and pharmacodynamics of artemether-lumefantrine. Clin Pharmacokinet. 1999 Aug;37(2):105-25.