Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects

Piperaquine (PQ) is an important partner drug in antimalarial combination treatments, but the long half-life of PQ raises concerns about drug resistance. Our aim was to investigate the extended antimalarial effect of PQ in a study of drug efficacy, reinoculation outcomes, and parasite viability after the administration of a single dose of PQ in the murine malaria model. Initially, male Swiss mice were inoculated with Plasmodium berghei and at 64 h after parasite inoculation were given PQ phosphate at 90 mg/kg of body weight intraperitoneally. Parasite viability, drug efficacy, reinoculation responses, and parasite resistance were determined at 25, 40, 60, 90, and 130 days after drug administration. At each time point, six mice were reinoculated with 10 7 P. berghei parasites and blood was harvested from another four mice for viability passage into naïve mice (n ‫؍‬ 5 for each blood sample) and from another two mice for determination of the plasma PQ concentration. The efficacy study demonstrated that the residual PQ concentrations did not suppress the infection after 25 days. Viable parasites were present up to 90 days after PQ dosing, although only 50% and 25% of the passaged parasites remained viable at 60 and 90 days postdosing, respectively. Viable parasites passaged into the naïve hosts were generally resistant to PQ when they were exposed to the drug for a second time. PQ was found to have a substantial antimalarial effect in this model, and the effect appears to be sufficient for a host immunological response to be established, resulting in the long-term survival of P. berghei-infected mice.Piperaquine (PQ) is a bisquinoline antimalarial drug used in contemporary artemisinin combination treatment (ACT) strategies as a partner to dihydroartemisinin (1, 4). In order to prevent drug resistance and early parasite recrudescence associated with the short-acting artemisinin drugs, ACT partner drugs should be long-acting schizonticides with half-lives (t 1/2 s) exceeding 4 days, or two asexual parasite life cycles (10,21). Recent pharmacokinetic studies have demonstrated that PQ has biphasic elimination and a long terminal t 1/2 of 12 to 28 days in humans (10,15,31,32).Several clinical trials of the PQ-dihydroartemisinin combination have shown that it has a high degree of efficacy and good tolerability for the treatment of Plasmodium falciparum infections (1,2,5,7,11,12,17). While this combination is now considered the first-line antimalarial treatment in some Southeast Asian countries, the long t 1/2 of PQ raises concerns about adverse effects and drug resistance (6,10,20,22). Detailed preclinical pharmacodynamic data for PQ, alone or in combination with artemisinin drugs, would complement clinical studies, especially when there is interest in the therapeutic impact of persistent, low PQ concentrations.We have recently demonstrated that PQ has a biphasic elimination profile in mice and has a terminal elimination t 1/2 in malaria parasite-infected and healthy mice of 18 days and 16 days, respectively (18). The ph...

supporting

confidence: 88%

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Moore

Ilett²,

Page‐Sharp³

et al. 2009

“…Most previous studies have used a two-compartment model (28,31,44). One study in healthy adults found that, although a three-compartment model represented the postadministration profile better, there were insufficient data to support its use over a two-compartment model (38). The mean elimination t 1/2 , a parameter influenced by the duration of sampling (45), was 512 h, a value within the previously reported range of 224 to 667 h (1,14,25,28,31,34,38,44).…”

Section: Discussionmentioning

confidence: 85%

“…One study in healthy adults found that, although a three-compartment model represented the postadministration profile better, there were insufficient data to support its use over a two-compartment model (38). The mean elimination t 1/2 , a parameter influenced by the duration of sampling (45), was 512 h, a value within the previously reported range of 224 to 667 h (1,14,25,28,31,34,38,44). Since there was substantial variability in the absorption phase of the plasma PQ concentration profile, a transit compartment model was tested and proved better than simpler absorption models that used lag time, as has been found in studies of other drugs (39).…”

Section: Discussionmentioning

confidence: 99%

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

Salman

Page‐Sharp

Batty

et al. 2012

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 ...

“…We kept our PNG women fasting for 2 h after dosing, and in a healthy volunteer population pharmacokinetic study in which Vietnamese subjects were also kept fasting for 2 h postdose, there was also no evidence of a time-dependent increase in bioavailability (46). Food intake was not controlled in the Thai study (14).…”

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.