Clinical and Pharmacological Determinants of the Therapeutic Response to Dihydroartemisinin-Piperaquine for Drug-Resistant Malaria

Price, Ric N.; Hasugian, Armedy Ronny; Ratcliff, A.; Siswantoro, Hadjar; Purba, Hermawan; Kenangalem, Enny; Lindegårdh, Niklas; Penttinen, Pasi; Laihad, Ferdinand; Ebsworth, E. P.; Anstey, Nicholas M.; Tjitra, Emiliana

doi:10.1128/aac.00486-07

Cited by 83 publications

(97 citation statements)

References 23 publications

(23 reference statements)

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“…Therefore, we conclude that in this murine malaria model the contribution of residual PQ concentrations of approximately 10 to 20 g/liter to the suppression of parasites was low, while PQ concentrations of Ͻ10 g/liter were ineffective. Although a direct comparison of the findings of the present study to those of studies with humans is not plausible, our findings are consistent with those in a recent report suggesting that plasma PQ concentrations of Ͼ30 g/liter are required for the successful treatment of clinical malaria (23). Hence, the malaria model could provide evidence for the concentration efficacy thresholds of other antimalarial drugs.…”

Section: Discussionsupporting

confidence: 82%

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Moore

Ilett²,

Page‐Sharp³

et al. 2009

Antimicrob Agents Chemother

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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...

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Section: Discussionsupporting

confidence: 82%

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Moore

Ilett²,

Page‐Sharp³

et al. 2009

Antimicrob Agents Chemother

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“…would be modest increases that can be achieved in the clinical setting, whereas the small predicted increase in piperaquine dose would not be practical. It is notable that recent clinical studies have recommended higher doses for piperaquine (11,13,14) and artesunate in children (15). Indeed, the doses proposed in the latter study closely match the allometric predictions of 3 mg/kg (15-kg child) and 2.8 mg/kg (25-kg child), based on scaling for dihydroartemisinin in the present study.…”

Section: Discussionsupporting

confidence: 74%

“…However, this linear method of dosage calculation is known to underestimate the optimum pediatric dose of many drugs (2)(3)(4)(5). Recent clinical reports indicate that higher doses of sulfadoxine-pyrimethamine (6, 7), chloroquine (6,8,9), quinine (10), piperaquine (11)(12)(13)(14), and artesunate (15,16) are required for effective antimalarial therapy in children.…”

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confidence: 99%

Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing

Senarathna

Batty

2014

Antimicrob Agents Chemother

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“…The current manufacturer's recommendation is for Artequick to be given as a 2-day regimen, which contrasts with the 3 days recommended for all ACTs by the WHO (48). Although the tolerability, safety, efficacy, and pharmacokinetics (PK) properties of DHA-PQ tetraphosphate have been widely investigated in children and adults (27,28,36,44,49), there are limited data relating to the efficacy and tolerability of 46) and no studies of the pharmacokinetics of this novel combination in malaria-infected patients. Concerns have been raised regarding possible underdosing in children for a number of antimalarial drugs (8,33), including PQ (27,36,49).…”

mentioning

confidence: 99%

“…Although the tolerability, safety, efficacy, and pharmacokinetics (PK) properties of DHA-PQ tetraphosphate have been widely investigated in children and adults (27,28,36,44,49), there are limited data relating to the efficacy and tolerability of ART-PQ base (37,46) and no studies of the pharmacokinetics of this novel combination in malaria-infected patients. Concerns have been raised regarding possible underdosing in children for a number of antimalarial drugs (8,33), including PQ (27,36,49). Although children have been included in studies of PQ pharmacokinetics (28,44), only one pharmacokinetic study of ART has specifically enrolled pediatric patients (40).…”

mentioning

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

Antimicrob Agents Chemother

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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 ...

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Clinical and Pharmacological Determinants of the Therapeutic Response to Dihydroartemisinin-Piperaquine for Drug-Resistant Malaria

Cited by 83 publications

References 23 publications

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Interspecies Allometric Scaling of Antimalarial Drugs and Potential Application to Pediatric Dosing

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

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