Pharmacokinetics of the Combination Pyrimethamine with Sulfadoxine and Mefloquine (FANSIMEF) in Chinese Volunteers and the Relative Bioavailability of a Lacquered Tablet
The oral single-dose pharmacokinetics and bioavailability of mefloquine (M) in combination with pyrimethamine (P) and sulfadoxine (S) from a single non-lacquered tablet (NL; M 250 mg, P 25 mg, S 500 mg) and two lacquered tablets (L; M 125 mg, P 12.5 mg, S 250 mg) were investigated in 6 healthy Chinese volunteers. The plasma concentrations of P and S were measured by high-performance liquid chromatography with UV detector over 11 days and the plasma concentrations of M were measured by gas chromatography with electron capture for 63 days. The pharmacokinetic evaluation of each of the three components was based on the assumption of an open linear one-compartment model. The model-independent pharmacokinetic parameters such as elimination half-life and total clearance of P and S in the present study were not appreciably different from those reported previously. The pharmacokinetic parameters of elimination half-life, total clearance and apparent volume of distribution of M were 11 days, 45.8 ml/h kg, and 14.8 1/kg, respectively. Compared to previously published data on M in Thai patients, Caucasian, Brazilian and African subjects, it was found that the elimination half-life in Chinese subjects was similar to that in Thai patients, but different from Caucasian, Brazilian and African subjects. There were significant differences in total clearance and volume of distribution among Chinese subjects and Thai patients. The differences in pharmacokinetic behaviour of M between subject groups needs to be examined further. The relative bioavailability of P, S, and M in the lacquered and non-lacquered tablet formulations in the 6 subjects studied were not significantly different with values (mean ± SD) of 0.98 ± 0.06,1.28 ± 0.20 and 1.02 ± 0.17, respectively. The combination of mefloquine (M) with pyrimethamine (P) and sulfadoxine (S; Fansimef) is an effective antimalarial in adults and children [1–3]. P and S inhibit two different enzymes (dihydrofolate reductase and dihydropterate synthetase) in the plasmodial folate biosynthesis pathway and the synergistic action of these drugs is enhanced by the additive effect of M, a quinoline methanol derivative [4]. The triple combination also delays the development of resistance [5] and in vitro studies confirm this efficacy even when there is a P-S resistance [6]. The pharmacokinetics of M in combination with P and S have been described in Brazilian [7], African [8], Caucasian [8, 9], and Thai patients [10] and Thai volunteers [11]. The present study investigates the pharmacokinetics of M in combination with P and S and the bioavailability of these drugs from non-lacquered and lacquered tablets in a cross-over design in 6 Chinese male volunteers.