Increased Risk of Early Vomiting among Infants and Young Children Treated with Dihydroartemisinin-Piperaquine Compared with Artemether-Lumefantrine for Uncomplicated Malaria

Abstract

Artemisinin-combination therapies (ACTs) currently represent first-line treatment of uncomplicated Plasmodium falciparum malaria throughout most of the world and exhibit excellent efficacy and the potential to minimize development of drug resistance.1 Of the numerous highly effective ACTs currently available, clinical choice often depends on adverse effect profiles, cost, and ease of administration.1 Artemetherlumefantrine (AL) is the most widely used ACT, accounting for 75% of the 100 million ACT treatments each year. Dihydroartemisinin-piperaquine (DP) is emerging as a favorable antimalarial option with comparable clinical efficacy to AL, prolonged post-treatment prophylaxis, and a simple once a day dosage regimen. 3-6The ACTs appear to be well-tolerated and serious toxicities are rare. 1,4,5,7 Early vomiting (vomiting within one hour of dosing) has been reported in 3% of courses of AL 4 and DP 4,6 in adults. However, this rate increased to 10% 6 or 11% 4 in children. Little tolerability data exists for ACTs in infants and young children in Africa, the most susceptible population to malaria-related morbidity and mortality. Early vomiting (vomiting within one hour of dosing) has been previously associated with younger age 4 and vomiting before treatment 6 and has been shown to reduce the effectiveness of non-ACT antimalarial therapies because of reduced drug absorption. Furthermore, vomiting after antimalarial drug administration may discourage patients from taking further doses of the medication. 9 The purpose of this study was to compare the risk of early vomiting after administration of AL or DP for the treatment of uncomplicated malaria in infants and young children in Africa.A total of 351 participants 6 weeks to 9 months of age were enrolled as part of a larger longitudinal cohort study in eastern Uganda. Participants received all medical care at a dedicated study clinic, which was open seven days a week. Episodes of uncomplicated malaria were diagnosed by positive thick blood smear, fever (tympanic temperature ≥ 38.0°C or history of fever within 24 hours), and absence of symptoms indicative of severe malaria. Participants were randomized to receive either AL (Co-artem; Novartis, Basel, Switzerland) or DP (Duo-cotecxin; Holleypharm, Chiongging City, People's Republic of China) at the time the first episode of uncomplicated malaria was diagnosed. Study participants received the same treatment regimen for all subsequent episodes of uncomplicated malaria diagnosed during the study period. All doses were administered with 150 mL of reconstituted milk (Nido; Nestle, Vevey, Switzerland) to ensure optimal absorption of lumefantrine and piperaquine.10-12 Details of the primary study have been reported. 3 As part of a pharmacokinetic substudy, detailed data on drug administration and early vomiting were recorded for all new cases of uncomplicated malaria that occurred during May 31-November 7, 2008.All DP doses and morning doses of AL were administered by study nurses, and participants were monitored for one hour....

Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria

“…Monitoring was adequate in three trials (Ashley 2004a THA; Tran 2004 VNM; Grande 2007 PER), and inadequate in one (Valecha 2010 AS), but incompletely reported in all four trials. No clinically important toxicities were reported (see Table 5).…”

“…We included 27 trials as primary references and retained seven trials as secondary references for additional data on secondary outcomes and adverse events. One of the 26 trials had two different recruitment settings which we split and considered as two separate trials (Ashley 2004a THA; Ashley 2004b THA). One trial (Borrmann 2011 KEN (a)) is pending as we await data for a separate recruitment period from the trial authors.…”

“…Five trials blinded laboratory staff (outcome assessors) to treatment allocation (Ashley 2004a THA; Ashley 2004b THA; Ashley 2005 THA; Smithuis 2010 MMR; Valecha 2010 AS). Patients were unblinded in all trials, and only one trial blinded outcome assessors for adverse effects (The 4ABC Study 2011 AF).…”

“…In a previous review of DHA-P, Myint 2007 noted an association between DHA-P and prolongation of the QT interval in two small observational trials (Karunajeewa 2004: N = 62, and Ashley 2004a THA; N = 32). Prolonged QT interval is a cardiac conduction defect which can sometimes lead to fatal arrhythmias.…”

Determination of The Antimalarial Drug Piperaquine in Small Volume Pediatric Plasma Samples by LC–MS/MS

“…DP is also under study for chemoprevention against malaria with monthly dosing for at-risk populations [2,3]. DP has performed well in treatment [4,5] and chemoprevention [2] trials, likely in part due to the long elimination half-life of PQ [6,7]. PQ (Figure 1), chemically named 1,3-bis-[4-(7-chloroquinolyl-4)-piperazinyl-1]-propane, is a weak base with four pKa values of 8.6, 8.6, 6.5 and 6.5 [8].…”