AimsTo study the population pharmacokinetics of piperaquine after co-administration with dihydroartemisinin in uncomplicated malaria. MethodsThe disposition of piperaquine was studied in 85 Cambodian patients with uncomplicated falciparum or vivax malaria treated with the piperaquine-dihydroartemisinin coformulation Artekin ® . All patients were given Artekin ® orally at 0, 6, 24 and 32 h with a total piperaquine dose of 32-35 mg base kg -1 . Adults were given tablets while children received either tablets or a dispersible granule formulation. Patients underwent either intensive (17-19 samples) or sparse (2-5 samples) blood sampling schedules over 35 days and clinical/parasitological follow-up over > 28 days. Piperaquine in plasma was quantified by high performance liquid chromatography. ResultsAll patients achieved fever clearance within 24 h and parasite clearance within 72 h. The 28-day cure rate was 97% in adults and 98% in children. A covariate-free twocompartment population model with first-order absorption and elimination gave the most robust representation of the plasma concentration-time data in both adults and children. In adults ( n = 38), the median (interquartile range) derived pharmacokinetic descriptors CL/ F , V ss / F and t 1/2,z were 0.9 l h -1 kg -1 (0.79-1.02 l h -1 kg -1 ), 574 l kg -1 (371-711 l kg -1 ) and 23 days (19-28 days), respectively. In children ( n = 47), corresponding values were 1.8 l h(332-1205 l kg -1 ) and 14 days (10-18 days), respectively. ConclusionsPiperaquine is a highly lipid-soluble drug with a large V ss / F , long t 1/2,z and a clearance that is markedly higher in children than in adults.

Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. For those occasions on which the oral route is possible, bioavailability may be altered by hypomotility, changes in gastrointestinal pH and enteral feeding. Hepatic and renal dysfunction are the primary determinants of drug clearance, and hence of steady-state drug concentrations, and of efficacy and toxicity in the individual patient. Oxidative metabolism is the main clearance mechanism for many drugs and there is increasing recognition of the importance of decreased activity of the hepatic cytochrome P450 system in critically ill patients. Renal failure is equally important with both filtration and secretion clearance mechanisms being required for the removal of parent drugs and their active metabolites. Changes in the steady-state volume of distribution are often secondary to renal failure and may lower the effective drug concentrations in the body. Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.

Aims To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria. Methods Twenty-six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non-compartmental methods. The time to 50% parasite clearance (PCT 50 ) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokineticpharmacodynamic relationships. Results Following i.v. bolus, ARTS had a peak concentration of 29.5 mm (11 mg l −1 ), elimination t 1/2 =2.7 min, CL=2.33 l h −1 kg −1 and V=0.14 l kg −1 .The C max for DHA was 9.3 mm (2.64 mg l . Following oral ARTS, relative bioavailability of DHA was 82%, C max was 2.6 mm (0.74 mg l −1 ), t 1/2 =39 min, and MAT=67 min. Overall, the PCT 50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT 50 or FCT and AUC, C max or MRT for DHA. Conclusions Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.