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.

The safety and efficacy of a novel combination of dihydroartemisinin (DHA) and piperaquine, Artekin (Holleykin Pharmaceuticals), were assessed in 106 patients (76 children and 30 adults) with uncomplicated falciparum malaria from 2 remote areas in Cambodia. Age-based doses were given at 0, 8, 24, and 32 h. Mean total DHA and piperaquine doses were 9.1 and 73.9 mg/kg, respectively, for children and 6.6 and 52.9 mg/kg for adults. All patients became aparasitemic within 72 h. Excluding the results for 1 child who died on day 4, there was a 96.9% 28-day cure rate (98.6% in children and 92.3% in adults). Patients who had recrudescent infection received low doses of Artekin. Side effects were reported by 22 patients (21%) but did not necessitate premature cessation of therapy. Although Artekin is a promising and inexpensive option for antimalarial therapy, further efficacy and pharmacokinetic studies are needed, especially for its use in children.

BackgroundIn Cambodia, estimates of the malaria burden rely on a public health information system that does not record cases occurring among remote populations, neither malaria cases treated in the private sector nor asymptomatic carriers. A global estimate of the current malaria situation and associated risk factors is, therefore, still lacking.MethodsA large cross-sectional survey was carried out in three areas of multidrug resistant malaria in Cambodia, enrolling 11,652 individuals. Fever and splenomegaly were recorded. Malaria prevalence, parasite densities and spatial distribution of infection were determined to identify parasitological profiles and the associated risk factors useful for improving malaria control programmes in the country.ResultsMalaria prevalence was 3.0%, 7.0% and 12.3% in Sampovloun, Koh Kong and Preah Vihear areas. Prevalences and Plasmodium species were heterogeneously distributed, with higher Plasmodium vivax rates in areas of low transmission. Malaria-attributable fevers accounted only for 10–33% of malaria cases, and 23–33% of parasite carriers were febrile. Multivariate multilevel regression analysis identified adults and males, mostly involved in forest activities, as high risk groups in Sampovloun, with additional risks for children in forest-fringe villages in the other areas along with an increased risk with distance from health facilities.ConclusionThese observations point to a more complex malaria situation than suspected from official reports. A large asymptomatic reservoir was observed. The rates of P. vivax infections were higher than recorded in several areas. In remote areas, malaria prevalence was high. This indicates that additional health facilities should be implemented in areas at higher risk, such as remote rural and forested parts of the country, which are not adequately served by health services. Precise malaria risk mapping all over the country is needed to assess the extensive geographical heterogeneity of malaria endemicity and risk populations, so that current malaria control measures can be reinforced accordingly.

AimsTo assess the haemodynamic, electrocardiographic and glycaemic effects of piperaquine-dihydroartemisinin (Artekin ® ) fixed combination therapy in uncomplicated malaria. MethodsSixty-two Cambodians (32 children and 30 adults) with falciparum or vivax malaria were given Artekin ® given as four age-based oral doses over 32 h. Supine and erect blood pressure, the electrocardiographic QT interval and plasma glucose were measured before treatment and then at regular intervals during a 4-day admission period as part of efficacy and safety monitoring. QT intervals were rate-corrected (QT c ) using Bazett's formula. Results Artekin® therapy was well tolerated and all patients responded to treatment. Average parasite and fever clearance times were 19 and 12 h, respectively. The pretreatment mean fall in systolic blood pressure on standing was 8 ± 6 mmHg and 6-hourly measurements over 72 h showed no significant change ( P = 0.48). There was a significant lengthening of the mean QT c to a maximum of 11 ms 0.5 (95% confidence interval 4-18 ms 0.5 ) relative to baseline at 24 h ( P = 0.003). The maximal QT c prolongation observed in any patient was 53 ms 0.5 . There was a mean 0.4 mmol l -1 reduction in the post-absorptive plasma glucose during the first 48 h but no episodes of hypoglycaemia (plasma glucose < 3.0 mmol l -1 ) were observed at any time. ConclusionsArtekin ® is safe and effective combination therapy for uncomplicated malaria in children and adults. Although piperaquine is a long half-life drug related to other quinoline compounds including chloroquine and quinine, no clinically significant cardiovascular or metabolic effects were observed.H. Karunajeewa et al. 9457 :1 Br J Clin Pharmacol

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