Piperaquine Pharmacodynamics and Parasite Viability in a Murine Malaria Model

Abstract

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...

Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model

“…4). Consistent with our previous reports of piperaquine in the murine malaria model (43,44), high-dose CQ led to a curative response. This outcome occurred at very low plasma concentrations several weeks after dosing (the value was unable to be extrapolated from the present study but was likely Ͻ1 g/liter) (Fig.…”

Modelling the time course of antimalarial parasite killing: a tour of animal and human models, translation and challenges

“…Batty et al . have detailed the murine parasite time course after dihydroartemisinin , chloroquine or piperaquine treatment , and have demonstrated enhanced magnitude and duration of antimalarial killing following combination therapy or multiple dosing. The disposition of dihydroartemisin in mice has been described by a one compartment model, with a short elimination half‐life of ∼0.3 h .…”

Mechanism-Based Model of Parasite Growth and Dihydroartemisinin Pharmacodynamics in Murine Malaria

“…The key advantage of using P. berghei in murine models is that all erythrocytic stages of the parasite life cycle are observable in thin blood films and are easily differentiated by light microscopy (10). Thus, murine malaria studies can generate robust PK-PD data, as has been reported for dihydroartemisinin (DHA) (14,15), chloroquine (16), and piperaquine (17), which could be used to optimize dosing. However, traditional animal studies do not allow the evaluation of all doses and are unable to dissect immune elimination of parasite or the contributions of individual antimalarials in combination therapy.…”