Efficacy and Day 7 Plasma Piperaquine Concentrations in African Children Treated for Uncomplicated Malaria with Dihydroartemisinin-Piperaquine

Abstract

BackgroundOne 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.MethodsWe 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.ResultsOf 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).ConclusionDHA-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.Trial RegistrationControlled-Trials.com ISRCTN59761234

Evidence of Plasmodium falciparum Malaria Multidrug Resistance to Artemisinin and Piperaquine in Western Cambodia: Dihydroartemisinin-Piperaquine Open-Label Multicenter Clinical Assessment

“…Indeed, it has been shown that this simplified measurement of exposure to PP is particularly suitable for long-half-life drugs and better than the total area under the curve (AUC) (31). In addition, several clinical studies have demonstrated that a day 7 plasma PP concentration of Ͻ30 ng/ml was associated with a higher risk of developing recurrent P. falciparum infections following DHA-PP treatment (27,32,33). In our study, we observed that the PP dose administered (in milligrams per kilogram) differed 3-fold (from 10 to 32 mg/kg/day) between patients and resulted in an 8-fold difference in plasma PP concentrations, but with no relationship between the two (see Fig.…”

Failure of dihydroartemisinin plus piperaquine treatment of falciparum malaria by under-dosing in an overweight patient

“…Indeed, WHO recommended the use of a PPQ dose of 1600 mg/day for body weigh above 80 kg [22]. In the literature, concerns have been raised over potential DP under-dosing in young children [28], and the 2013 Worldwide Antimalarial Resistance Network (WWARN) has explored the relationship between weight-adjusted DP dosage (mg/kg) and therapeutic efficacy in a meta-analysis [23]. Data of 7072 patients from prospective studies investigating DP efficiency were pooled.…”

Treatment outcomes in a safety observational study of dihydroartemisinin/piperaquine (Eurartesim®) in the treatment of uncomplicated malaria at public health facilities in four African countries

“…Despite the longer half-life of PQ, new infections have been reported within a few weeks of treatment with DHA-PQ, particularly in children age 2–10 years because of their higher body weight-normalized clearance. This leads to lower PQ exposure compared to older persons with lower day 7 PQ concentrations after standard weight-based dosing [ 14 , 15 ]. This effect has been associated with an increased risk of recurrent parasitaemia [ 14 ].…”

“…This leads to lower PQ exposure compared to older persons with lower day 7 PQ concentrations after standard weight-based dosing [ 14 , 15 ]. This effect has been associated with an increased risk of recurrent parasitaemia [ 14 ].…”