The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers

Pharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC 0 -ؕ ), with medians of 49,451 (n ‫؍‬ 12) and 44,556 (n ‫؍‬ 22) g · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC 0 -ؕ was 1,652 g · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.T he most recent World Health Organization (WHO) recommendations for the treatment of uncomplicated malaria include a 3-day course of dihydroartemisinin plus piperaquine (DHA-PQ) as a first-line artemisinin (ART) combination therapy (ACT) (48). Various formulations of DHA-PQ are marketed in tropical countries (Duo-cotecxin, Combimal, and P-Alaxin; http://www.actwatch.info /resources/drugs_home03_search.asp) or are in development (Eurartesim) (20), and all employ PQ tetraphosphate as the DHA partner drug. DHA is a semisynthetic derivative of ART, and its production adds to the manufacturing cost, but, unlike ART, it does not exhibit autoinduction of metabolism. In addition, although the tetraphosphate salt of PQ has greater water solubility and therefore may have better oral bioavailability, incorporation of the lipid-soluble PQ base should also simplify production.Artequick (Artepharm Co. Ltd., Guangzhou, China) is an ACT that contains ART in place of DHA and PQ base rather than PQ tetraphosphate. This combination is formulated as tablets but also as granules for pediatric use. It is marketed in ...

Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 85%

Section: Methodsmentioning

confidence: 99%

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

Salman

Page‐Sharp

Batty

et al. 2012

“…Food intake was not controlled in the Thai study (14). Although a small amount of fat (Ͻ10 g) does not increase PQ bioavailability (47)(48)(49), greater fat intake, such as that associated with a normal meal, can as much as double relative bioavailability (50)(51)(52). It is possible that the women in the Thai study, whether pregnant or not, consumed increasing amounts of fat as they recovered from malaria, progressively increasing bioavailability as a result of the lipophilicity of PQ.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics, Tolerability, and Safety of Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine-Piperaquine in Pregnant and Nonpregnant Papua New Guinean Women

Benjamin

Moore

Salman

et al. 2015

The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC 0 -ؕ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.

“…considerably between doses, which could be explained by variation in mean transit time (45.8%) and in relative bioavailability (56.3%). Piperaquine is a lipophilic compound with a low oral bioavailability (50% in the rat) (57) and variable food-dependent absorption and thus total exposure (3,16,41,53). Food intake was not controlled in this study, which might explain part of the high intraindividual variability observed in absorption parameters.…”

Section: Figmentioning

confidence: 99%

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

Tärning

Rijken

McGready

et al. 2012

140

c Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series. Children under the age of 5 years and pregnant women are especially vulnerable to malaria. An estimated 85 million pregnancies occurred in areas with falciparum malaria transmission during 2007 (13). Malaria during pregnancy is responsible for maternal and fetal mortality (42,43). Both falciparum malaria and vivax malaria during pregnancy are associated with low birth weight resulting from intrauterine growth restriction (8, 9, 48). Effective treatment and prophylaxis of malaria in pregnancy rely on the use of efficacious antimalarial drugs.Pregnancy has substantial effects on the pharmacokinetic characteristics of many antimalarial drugs. Previous studies report artesunate, artemether, dihydroartemisinin, sulfadoxine, atovaquone, proguanil, cycloguanil, pyrimethamine, and lumefantrine concentrations to be reduced in pregnant women (25,33,34,36,44,58). This may contribute to lower antimalarial cure rates in pregnant than nonpregnant adults (58). Other studies report no pharmacokinetic differences in pregnant women compared to nonpregnant women (e.g., pyrimethamine and amodiaquine/desethylamodiaquine) or even a higher drug exposure during pregnancy (pyrimethamine) (15,25,46).Artemisinin-based combi...