Safety, Tolerability, and Single‐ and Multiple‐Dose Pharmacokinetics of Piperaquine Phosphate in Healthy Subjects

Abstract

Piperaquine phosphate is an orally active bisquinolone antimalarial drug that has been used for the past 3 decades. The authors report the safety, tolerability, and pharmacokinetics of piperaquine from a classical controlled phase I study. It was a double-blind, randomized, parallel-group, placebo-controlled, and single- and multiple-dose study. During the rising single-dose study, single ascending oral doses of 500, 750, 1000, 1250, and 1500 mg of piperaquine phosphate were administered, whereas in rising multiple-dose study, once-daily ascending oral doses of 500, 750, 1000, and 1500 mg were administered for 3 consecutive days. Pharmacokinetic analysis for both the rising single- and multiple-dose studies was done using the noncompartmental approach. The mean apparent terminal half-life ranged from 11 to 23 days. Increase in exposure was less than dose proportional and linear. Piperaquine concentrations were measurable up to 60 days postdose. Multiple peaks were observed in the plasma piperaquine concentration-time profiles and exhibited 3- to 7-fold accumulation following multiple dosing. Piperaquine was well tolerated following single and multiple doses.

Pharmacokinetics and Bioequivalence Evaluation of Two Fixed-Dose Tablet Formulations of Dihydroartemisinin and Piperaquine in Vietnamese Subjects

“…The geometric mean C max (232 versus 204 ng/ml) and AUC 03last (13,431 versus 11,988 ng ⅐ h/ml) of piperaquine were higher after Arterakine than after Artekin administration, but the difference was not significant. After adjusting for dose and weight differences, the C max of piperaquine was markedly higher in the healthy Vietnamese subjects after the administration of both ACTs than in healthy Caucasians administered piperaquine alone (1,16). Ethnic differences and differences in tablet excipients and dissolution behavior may account for the variations in piperaquine concentrations achieved after the administration of piperaquine alone and the two coformulations used in the present study.…”

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

“…One study in healthy adults found that, although a three-compartment model represented the postadministration profile better, there were insufficient data to support its use over a two-compartment model (38). The mean elimination t 1/2 , a parameter influenced by the duration of sampling (45), was 512 h, a value within the previously reported range of 224 to 667 h (1,14,25,28,31,34,38,44). Since there was substantial variability in the absorption phase of the plasma PQ concentration profile, a transit compartment model was tested and proved better than simpler absorption models that used lag time, as has been found in studies of other drugs (39).…”

“…The minimum values of the objective function (OFV) and conditional weighted residuals (CWRES) plots were used to choose suitable models during the model-building process. Allometric scaling was employed a priori, with volume terms multiplied by (WT/70) 1.0 and clearance terms by (WT/70) 0.75 (3), where WT represents total body weight. Residual variability (RV) data were estimated as additive errors for the log-transformed data.…”

A Small Amount of Fat Does Not Affect Piperaquine Exposure in Patients with Malaria

“…Despite the long history of piperaquine use, its pharmacokinetic properties have been characterized only in recent years. Piperaquine is a highly lipophilic bisquinoline compound with a large apparent volume of distribution of approximately 500 liters/kg, low oral clearance of approximately 1 liter/h/kg, and a consequently long terminal elimination half-life of more than 20 days (1,14,(26)(27)(28).…”