Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria

Abstract

Aims: To study the population pharmacokinetics of piperaquine after co-administration with dihydroartemisinin in uncomplicated malaria.

Methods: The 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.

Results: All 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 two-compartment 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, Vss/F and t1/2,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-1 kg-1 (1.29-2.3 l h-1 kg-1), 614 l kg-1 (332-1205 l kg-1) and 14 days (10-18 days), respectively.

Conclusions: Piperaquine is a highly lipid-soluble drug with a large Vss/F, long t1/2,z and a clearance that is markedly higher in children than in adults.

Figure 1

Piperaquine phosphate – 1,3-bis[1-(7-chloro-4′-quinolyl)-4′-piperazinyl] phosphate

Figure 2

Plots of weighted residuals against predicted piperaquine concentrations for datasets from (A) adults and (B) children. Residuals were approximately evenly distributed above and below zero (solid line). Homoscedastic and heteroscedastic weighted error models were used for the adult and children datasets, respectively

Figure 3

Observed plasma piperaquine concentration-time data for adults (A) and children (B). The solid lines show simulated concentration-time data (solid line) derived from the mean pharmacokinetic parameters (Table 5) and the average doses (Table 2). The dotted line indicates the assay limit of quantification (LOQ; 5 µg l⁻¹). Note that concentrations below the LOQ do not contribute to the regression analysis. The biphasic appearance of the simulated curves within the first 3 days results from the close proximity of doses 1 and 2, and 3 and 4 (see Methods)