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) μg · 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 μg · 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.

Fig 1

(A) Population (○) and individual (●) predicted versus observed plasma piperaquine concentrations (in micrograms per liter on a log₁₀ scale) for the final model. The line of identity is also shown. (B) Conditional weighted residuals versus time (log scale) for piperaquine final model.

Fig 2

Visual predictive check showing observed 50th (●), 10th (◇), and 90th (○) percentiles with simulated 95% CIs for the 50th (solid black line), 10th (gray dotted lines), and 90th (dashed gray lines) percentiles for plasma piperaquine concentrations (micrograms per liter on a log₁₀ scale) versus time (h) for Artequick (A) and Duo-cotecxin (B) from the final model. The observed data are superimposed as gray crosses. The inset shows data for the first 96 h.

Fig 3

(A) Population (○) and individual (●) predicted versus observed plasma artemisinin concentrations (micrograms per liter on a log₁₀ scale) for the final model. The line of identity is also shown. (B) Conditional weighted residuals versus time for artemisinin final model.

Fig 4

Visual predictive check showing observed 50th (●), 10th (♢), and 90th (○) percentiles with simulated 95% CIs for the 50th (solid black line), 10th (gray dotted lines), and 90th (dashed gray lines) percentiles for plasma artemisinin concentrations (micrograms per liter on a log₁₀ scale) versus time (h) from the final model. The observed data are superimposed as gray crosses.