Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine. METHODS AND FINDINGS: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. CONCLUSIONS: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015)

Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.

BACKGROUND: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. METHODS: Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. RESULTS: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations 200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. CONCLUSIONS: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study.

BACKGROUND:The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children. METHODS:Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1-2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose). RESULTS:Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention. CONCLUSIONS:Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs

DP weight-based dosing guidelines.

<p>DP weight-based dosing guidelines.</p

Predictions related to trough and peak capillary plasma concentration of PQ at steady-state with various chemoprevention regimens of DP in 1–2 year olds weighing ≥ 11 kg.

<p>Predictions related to trough and peak capillary plasma concentration of PQ at steady-state with various chemoprevention regimens of DP in 1–2 year olds weighing ≥ 11 kg.</p

Comparative predicted capillary plasma PQ concentrations with and without a loading dose of DP and predicted maximum concentration with a loading dose of DP in 1–2 year olds weighing ≥ 11 kg.

<p>Comparative predicted capillary plasma PQ concentrations with and without a loading dose of DP and predicted maximum concentration with a loading dose of DP in 1–2 year olds weighing ≥ 11 kg.</p