Clinical Pharmacokinetics of Mefloquine

Abstract

Mefloquine, a quinoline-methanol antimalarial, is effective single dose therapy for all species of malaria infecting humans, including multi-drug-resistant Plasmodium falciparum. It is used both in prophylaxis and treatment. Mefloquine is available either as the hydrochloride salt alone, or in a combined preparation with sulfadoxine and pyrimethamine. There is no parenteral formulation. Several assay methodologies have been developed, but high performance liquid chromatography has been the most used in recent pharmacokinetic studies. These have shown in healthy volunteers that mefloquine is absorbed with a half-life of 1 to 4 hours and a time to peak concentration of 7 to 24 hours (median 16.7 hours). Mean peak blood concentrations have ranged between 50 and 110 (median 83) ng/ml/mg/kg. Estimates of total apparent volume of distribution (Vd/f) have ranged from 13.3 to 40.9 (median 19.2) L/kg, systemic clearance (CL/f) from 0.022 to 0.073 L/h/kg (median 0.026 L/h/kg), and terminal elimination half-life from 13.8 to 40.9 days (median 20 days). Systemic clearance appears to be increased in late pregnancy. In uncomplicated falciparum malaria, peak blood concentrations are 2 to 3 times higher than those in healthy subjects ranging from 112 to 209 (median 144) ng/ml/mg/kg because of contraction in the total apparent volume of distribution. Systemic clearance is usually reduced but elimination rates are increased (possibly because of reduced enterohepatic recycling). Mefloquine absorption appears to be reduced in severe falciparum malaria; plasma protein binding exceeds 98% in both healthy subjects and patients. No important drug interactions have been identified as yet, but the potential for serious interactions with quinine has not been adequately investigated. More studies are needed on the disposition of mefloquine in children.

Mefloquine as a potential drug against multidrug-resistant tuberculosis

“…Following oral administration of mefloquine, about 75-80% of the drug is absorbed, and time to peak concentration were found to be 7-24 h [7,8]. There is little pre-systemic metabolism of the compound, which has a terminal elimination half-life of 14-41 days (medium 20 days) [7].…”

“…There is little pre-systemic metabolism of the compound, which has a terminal elimination half-life of 14-41 days (medium 20 days) [7]. Mefloquine is quickly distributed throughout the body, and has a high affinity for lipids; in blood plasma it is essentially protein-bound.…”

Population Pharmacokinetic Assessment of a New Regimen of Mefloquine Used in Combination Treatment of Uncomplicated Falciparum Malaria

“…Mefloquine is moderately well absorbed orally and extensively distributed and is Ͼ98% bound to plasma proteins. The terminal elimination half-life is approximately 3 weeks for healthy subjects and 2 weeks for subjects with malaria (6). The main metabolite identified in man is 2-8-bis-trifluoromethyl-4-quinoline carboxylic acid (MMQ), which is inactive against Plasmodium falciparum.…”

In vitro blood schizonticidal activity of sera containing mefloquine‐quinine against Plasmodium falciparum

“…Following the QN alone regimen, maximum activity was evident at 1.5-4 hours, suggested by the highest range of MID. The patterns of serum activities coincided on all occasions with their pharmacokinetic properties, showing relatively long and sustained blood schizonticidal activity of MQ in the body (half-life of 14-20 days) compared with QN (half-life of 12-16 h) (Karbwang & White, 1990;Karbwang et al 1993). MQ seems to act at an earlier stage (early rings) and with greater potency than QN.…”