Pharmacokinetic Comparison of Two Piperaquine-Containing Artemisinin Combination Therapies in Papua New Guinean Children with Uncomplicated Malaria

Abstract

Pharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC 0 -ؕ ), with medians of 49,451 (n ‫؍‬ 12) and 44,556 (n ‫؍‬ 22) g · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC 0 -ؕ was 1,652 g · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.T he most recent World Health Organization (WHO) recommendations for the treatment of uncomplicated malaria include a 3-day course of dihydroartemisinin plus piperaquine (DHA-PQ) as a first-line artemisinin (ART) combination therapy (ACT) (48). Various formulations of DHA-PQ are marketed in tropical countries (Duo-cotecxin, Combimal, and P-Alaxin; http://www.actwatch.info /resources/drugs_home03_search.asp) or are in development (Eurartesim) (20), and all employ PQ tetraphosphate as the DHA partner drug. DHA is a semisynthetic derivative of ART, and its production adds to the manufacturing cost, but, unlike ART, it does not exhibit autoinduction of metabolism. In addition, although the tetraphosphate salt of PQ has greater water solubility and therefore may have better oral bioavailability, incorporation of the lipid-soluble PQ base should also simplify production.Artequick (Artepharm Co. Ltd., Guangzhou, China) is an ACT that contains ART in place of DHA and PQ base rather than PQ tetraphosphate. This combination is formulated as tablets but also as granules for pediatric use. It is marketed in ...

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

“…As found previously (39), there was significant variability in the absorption phase of PQ. Therefore, a transit compartment model, previously shown to be effective in characterizing the absorption phase of PQ (39), was also tested.…”

“…As found previously (39), there was significant variability in the absorption phase of PQ. Therefore, a transit compartment model, previously shown to be effective in characterizing the absorption phase of PQ (39), was also tested. In this model, the dose passes through a series of transit compartments before entering the absorption compartment, in order to model the delay often associated with drug absorption.…”

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

“…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).…”

“…There is no significant difference in piperaquine clearance when piperaquine is administered alone or in combination with dihydroartemisinin (148). 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).…”

“…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.…”