Dataset Information

Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria.

ABSTRACT: This prospective trial investigated the population pharmacokinetics of piperaquine given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard 3-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three-compartment model with first-order absorption described the data well. Age had a statistically significant effect (P < 0.005) on clearance/bioavailability in a model that accounts for allometric scaling. Simulations demonstrated that higher doses in all children, but especially in those with lower weight for age, are required for adequate piperaquine exposure, although safety and tolerance will need to be established. These findings support other evidence that both weight- and age-specific guidelines for piperaquine dosing in children are urgently needed.

SUBMITTER: Sambol NC

PROVIDER: S-EPMC5088713 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria.

Sambol N C NC Yan L L Creek D J DJ McCormack S A SA Arinaitwe E E Bigira V V Wanzira H H Kakuru A A Tappero J W JW Lindegardh N N Tarning J J Nosten F F Aweeka F T FT Parikh S S

Clinical pharmacology and therapeutics 20150502 1

This prospective trial investigated the population pharmacokinetics of piperaquine given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age group previously unstudied. Current weight-based dosing does not adequately address physiological changes in early childhood. Patients were administered standard 3-day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/ ...[more]

PMID: 25732044

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Project description:One promising new Artemisinin-based combination therapies (ACTs) is dihydroartemisinin-piperaquine (DHA-PQ). However, the pharmacokinetics of piperaquine and the relationship between drug levels and clinical efficacy are incompletely characterized, particularly in children.We performed a single-arm open-label trial in Bobo-Dioulasso, Burkina Faso. A total of 379 participants aged 6 months or more with uncomplicated falciparum malaria were enrolled. Each participant received daily dose of DHA-PQ for three days and followed for 42 days. Parasitological efficacy was analyzed, considering rates of recrudescence and overall recurrence. PK was an exploratory endpoint and a priori, no sample size had been determined. Day 7 capillary and venous plasma concentrations of piperaquine were measured in children aged 2-10 years.Of the 379 participants, 365 (96.3%) completed 42 days of follow-up. The median daily dose of PQ was 18.5 mg/kg [6.5-24]. Treatment with DHA-PQ was well tolerated with fever and parasitemia resolution within 48 hours in nearly all children. Recurrent malaria within 42 days of follow-up occurred in 31.3% (10/34) of children less than 2 years old, 16.0% (16/106) of those aged 2-5 years, 9.4% (15/160) of those aged 5-10 years, and none (0/68) of those over 10 years old. After genotyping, 3 of 41 recurrent episodes were recrudescence. An exploratory analysis shows that children with successful treatment outcomes had significantly higher median plasma concentrations of PQ compared to those with recurrent malaria within 42 days after therapy, considering either capillary samples (68 ng/ml [50-85] compared to 48 ng/ml [36-55], p<0.001) or venous samples (42 ng/ml [29-59] compared to 25 ng/ml [19-44], p<0.001).DHA-PQ was effective for uncomplicated P. falciparum malaria treatment and offers an alternative to other ACTs. Recurrent malaria was mainly due to new infections after treatment and was correlated with low day 7 PQ concentration in the youngest patients.Controlled-Trials.com ISRCTN59761234.

Project description:BackgroundAnti-malarial chemoprevention with dihydroartemisinin-piperaquine (DHA/PQ) is a promising tool for malaria control, but its efficacy in children may be limited by inadequate drug exposure.MethodsChildren were enrolled in a non directly-observed trial of DHA/PQ chemoprevention in a high transmission setting in Uganda. Children were randomized at 6 months of age to no chemoprevention (n = 89) or monthly DHA/PQ (n = 87) and followed through 24 months of age, with pharmacokinetic sampling performed at variable times following monthly dosing of DHA/PQ. A previously published pharmacokinetic model was used to estimate piperaquine (PQ) exposure in each child, and associations between PQ exposure and the protective efficacy (PE) of DHA/PQ were explored.ResultsThe incidence of malaria was 6.83 and 3.09 episodes per person year at risk in the no chemoprevention and DHA/PQ arms, respectively (PE 54 %, 95 % CI 39-66 %, P < 0.001). Among children randomized to DHA/PQ, 493 pharmacokinetic samples were collected. Despite nearly 100 % reported adherence to study drug administration at home, there was wide variability in PQ exposure, and children were stratified into three groups based on average PQ exposure during the intervention that was determined by model generated percentiles (low, n = 40; medium, n = 37, and high, n = 10). Gender and socioeconomic factors were not significantly associated with PQ exposure. In multivariate models, the PE of DHA/PQ was 31 % in the low PQ exposure group (95 % CI 6-49 %, P = 0.02), 67 % in the medium PQ exposure group (95 % CI 54-76 %, P < 0.001), and 97 % in the high PQ exposure group (95 % CI 89-99 %, P < 0.001).ConclusionsThe protective efficacy of DHA/PQ chemoprevention in young children was strongly associated with higher drug exposure; in children with the highest PQ exposure, monthly DHA/PQ chemoprevention was nearly 100 % protective against malaria. Strategies to ensure good adherence to monthly dosing and optimize drug exposure are critical to maximize the efficacy of this promising malaria control strategy.Trial registrationCurrent Controlled Trials Identifier NCT00948896.

Dataset Information

Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria.

Publications

Population Pharmacokinetics of Piperaquine in Young Ugandan Children Treated With Dihydroartemisinin-Piperaquine for Uncomplicated Malaria.

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