Piperaquine is a bisquinoline antimalarial drug that was first synthesised in the 1960s, and used extensively in China and Indochina as prophylaxis and treatment during the next 20 years. A number of Chinese research groups documented that it was at least as effective as, and better tolerated than, chloroquine against falciparum and vivax malaria, but no pharmacokinetic characterisation was undertaken. With the development of piperaquine-resistant strains of Plasmodium falciparum and the emergence of the artemisinin derivatives, its use declined during the 1980s. However, during the next decade, piperaquine was rediscovered by Chinese scientists as one of a number of compounds suitable for combination with an artemisinin derivative. The rationale for such artemisinin combination therapies (ACTs) was to provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability that would reduce transmission and protect against the development of parasite resistance. This approach has now been endorsed by the WHO. Piperaquine-based ACT began as China-Vietnam 4 (CV4): dihydroartemisinin [DHA], trimethoprim, piperaquine phosphate and primaquine phosphate), which was followed by CV8 (the same components as CV4 but in increased quantities), Artecom (in which primaquine was omitted) and Artekin or Duo-Cotecxin (DHA and piperaquine phosphate only). Recent Indochinese studies have confirmed the excellent clinical efficacy of piperaquine-DHA combinations (28-day cure rates >95%), and have demonstrated that currently recommended regimens are not associated with significant cardiotoxicity or other adverse effects. The pharmacokinetic properties of piperaquine have also been characterised recently, revealing that it is a highly lipid-soluble drug with a large volume of distribution at steady state/bioavailability, long elimination half-life and a clearance that is markedly higher in children than in adults. The tolerability, efficacy, pharmacokinetic profile and low cost of piperaquine make it a promising partner drug for use as part of an ACT.

Piperaquine (PQ) is an antimalarial drug whose high lipid solubility suggests that its absorption can be increased by a high-fat meal. We examined the pharmacokinetics of PQ phosphate (500 mg given orally) in the fasting state and after a high-fat meal in eight healthy Caucasian volunteers (randomized crossover). Plasma PQ concentration-time profiles were analyzed by using noncompartmental pharmacokinetic analysis. In the fed state, the geometric mean C max increased by 213%, from 21.0 to 65.8 g/liter (P < 0.001). The time of C max was not significantly different between the fasting and fed states. The geometric mean area under the concentration-time curve from zero onward (AUC 0-ؕ ) increased by 98%, from 3,724 to 7,362 g h/liter (P ‫؍‬ 0.006). The oral bioavailability of PQ relative to the fasting state was 121% greater after the high-fat meal (95% confidence interval, 26 to 216% increase; P ‫؍‬ 0.020). The side effects, postural blood pressure changes, electrocardiographic corrected QT interval, serum glucose, and other biochemical and hematological indices were similar in the fasting and fed states over 28 days of follow-up.Piperaquine (PQ) is a bisquinoline antimalarial drug that was first synthesized in the 1950s (10). It was less toxic than chloroquine (25), and its efficacy against chloroquine-resistant strains of Plasmodium falciparum led to its widespread distribution in China and Indochina in the 1970s as prophylaxis and treatment (6,14). With the emergence of PQ-resistant parasite strains, its use declined (4,13,20), but the search for a suitable partner drug as part of artemisinin-based combination therapy (ACT) has led to a resurgence of interest in PQ. Fixed dose combinations of PQ with dihydroartemisinin (DHA) are registered and marketed in China and Vietnam (10).Despite the fact that PQ has been in clinical use for over 30 years, its pharmacokinetics in malaria have only recently been described (16,17). The disposition of oral PQ given to Cambodian patients in recommended doses was best described by a two-compartment model with first-order absorption. In adults, the absorption half-life (t 1/2abs ), volume of distribution at pseudodistribution equilibrium relative to bioavailability (V ss / F), apparent oral clearance (CL/F), and elimination half-life (t 1/2␤ ) were 9.1 h, 574 liter/kg, 0.9 liter/h/kg, and 543 h, respectively, whereas in children these variables had mean values of 9.3 h, 614 liter/kg, 1.85 liter/h/kg, and 324 h, respectively. The long t 1/2abs and high oil-to-water partition ratio of PQ (3) strongly suggest that its absorption is limited by its high lipid solubility. Since the oral bioavailability of other moderate to highly lipid-soluble antimalarial drugs, including mefloquine, atovaquone, and halofantrine, is increased by administration with a high-fat meal (8, 21, 23), we hypothesized that this would also apply to PQ.The aim of the present study was, therefore, to determine the effects of a high-fat meal on the oral bioavailability of PQ in healthy Caucasian volunteers. Seco...