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.
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.
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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