Population Pharmacokinetics and Pharmacodynamics of Piperaquine in Children With Uncomplicated Falciparum Malaria

Abstract

Dihydroartemisinin-piperaquine is being increasingly used as a first-line artemisinin combination treatment for malaria. The aim of this study was to describe the pharmacokinetic and pharmacodynamic properties of piperaquine in 236 children with uncomplicated falciparum malaria in Burkina Faso. They received a standard body weight-based oral 3-day fixed-dose dihydroartemisinin-piperaquine regimen. Capillary plasma concentration-time profiles were characterized using nonlinear mixed-effects modeling. The population pharmacokinetics of piperaquine were described accurately by a two-transit-compartment absorption model and a three-compartment distribution model. Body weight was a significant covariate affecting clearance and volume parameters. The individually predicted day 7 capillary plasma concentration of piperaquine was an important predictor (P < 0.0001) of recurrent malaria infection after treatment. Young children (2-5 years of age) received a significantly higher body weight-normalized dose than older children (P = 0.025) but had significantly lower day 7 piperaquine concentrations (P = 0.024) and total piperaquine exposures (P = 0.021), suggesting that an increased dose regimen for young children should be evaluated.

Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing

“…would be modest increases that can be achieved in the clinical setting, whereas the small predicted increase in piperaquine dose would not be practical. It is notable that recent clinical studies have recommended higher doses for piperaquine (11,13,14) and artesunate in children (15). Indeed, the doses proposed in the latter study closely match the allometric predictions of 3 mg/kg (15-kg child) and 2.8 mg/kg (25-kg child), based on scaling for dihydroartemisinin in the present study.…”

“…The piperaquine data appear to be conflicting; however, there were several clinical differences between the two populations and no conclusive explanation for the findings (56,57). Two recent reports of piperaquine pharmacokinetics showed lower CL/F values, suggesting that the rule of exponents may be applicable to piperaquine, but as noted in Table 4, these data could not be included in the present study due to the use of pooled results from different partner drugs (12) and use of capillary blood analysis to determine the pharmacokinetic parameters (13). Quinine predictions are problematic, due to the difference in CL (and V z ) between healthy subjects and patients with malaria, and the reported lower CL in children than adults (Table 3).…”

“…One recent study reported a CL/F of 0.57 liter/h/kg; however, the data were pooled from a previous study of piperaquine-dihydroartemisinin (57) and an investigation of piperaquine-artemisinin (12). A report of a piperaquine CL/F of 0.42 liter/h/kg from capillary blood samples could not be compared directly to investigations using venous plasma samples for determination of piperaquine pharmacokinetic parameters (13). d Mefloquine CL/F was determined from studies of mefloquine-sulfadoxine-pyrimethamine in malaria-infected children.…”

“…However, this linear method of dosage calculation is known to underestimate the optimum pediatric dose of many drugs (2)(3)(4)(5). Recent clinical reports indicate that higher doses of sulfadoxine-pyrimethamine (6, 7), chloroquine (6,8,9), quinine (10), piperaquine (11)(12)(13)(14), and artesunate (15,16) are required for effective antimalarial therapy in children.…”

Making the Most of Clinical Data: Reviewing the Role of Pharmacokinetic-Pharmacodynamic Models of Anti-malarial Drugs

“…Another example is lumefantrine, where the absorption of the drug was observed to increase if co-administered with fat (51). More recently, population PK modeling has suggested higher doses of oral piperaquine (52) and intra-muscular artesunate (53) Table S2 and Eq. S5 of reference)…”