Pharmacokinetics and pharmacodynamics of piperaquine in a murine malaria model

Abstract

Piperaquine (PQ) is an important partner in antimalarial treatment strategies. However, there is a paucity of detailed preclinical and pharmacokinetic data to link PQ serum concentrations and toxicity or efficacy. The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of PQ in a murine malaria treatment model. The study comprised three arms. (i) PQ pharmacokinetic parameters were determined in healthy and malaria-infected mice (90 mg/kg PQ phosphate [PQP]). (ii) For determination of single-dose pharmacodynamics, Swiss mice were inoculated with Plasmodium berghei parasites and given PQP (10, 30, or 90 mg/kg intraperitoneally) at 2 to 5% starting parasitemia. After 60 days, the 90-mg/kg PQP group was reinoculated with P. berghei. (iii) Combination efficacy was investigated at doses of 10 mg/kg PQP and 30 mg/kg dihydroartemisinin (DHA). The median survival times were 4, 10, and 54 days for 0, 10, and 30 mg/kg PQP, respectively. All mice given 90 mg/kg PQP survived beyond 60 days, with a mean parasitemia of <1% before and after reinoculation. The nadir for DHA plus PQP was significantly lower (22-fold +/- 12-fold) than the initial parasitemia for the individual drugs (DHA, 12-fold +/- 5-fold; PQP, 13-fold +/- 3-fold; P = 0.007 [analysis of variance]). The elimination half-lives of PQ in healthy and infected mice were 18 and 16 days, respectively, and the extrapolated residual PQ concentration at 60 days (<10 mug/liter) was ineffective at suppressing P. berghei infection. PQ has a potent antimalarial effect after single-dose treatment, and its efficacy was enhanced by combination with DHA.

FIG. 1.

Concentration-time profile of PQ in mice given PQP at approximately 90 mg/kg i.p. (normalized for pharmacokinetic analysis; see Materials and Methods for details). Data are given as mean ± SD plasma PQ concentrations (n = 5) in healthy (○) and malaria-infected (▴) mice. The lines represent the best fit of a two-compartment model to the respective data sets (extrapolated beyond the last data point for healthy mice [25 days] to facilitate comparisons).

FIG. 2.

Parasitemia-time profile in Swiss mice following the administration of a single i.p. dose of PQP administered 64 h after inoculation with 10⁷ P. berghei-parasitized erythrocytes. Data are shown as total parasitemia (mean percentage of erythrocytes infected ± SD), commencing from the time of PQP administration. Symbols: •, control (n = 8); ○, 10 mg/kg (n = 14); ▵, 30 mg/kg (n = 13); ▪, 90 mg/kg (n = 14). Panel B shows an expanded view for the first 5 days after drug administration.

FIG. 3.

Parasitemia-time profile in Swiss mice following the administration of a single dose of PQP (90 mg/kg; n = 14; ▪) at time zero and after subsequent reinoculation with 10⁷ P. berghei-parasitized erythrocytes at 60 days. Data are shown as total parasitemia (mean percentage of erythrocytes infected ± SD). Three control groups studied at the 60-day point comprised uninfected Swiss mice that were age matched and inoculated for the first time after 60 days, i.e., untreated at day 0 (n = 4; •); vehicle treated at day 0 (n = 4; ○); and treated with PQP at 90 mg/kg at day 0 (n = 4; ▵).

FIG. 4.

Parasitemia-time profiles in mice as a proportion of the initial parasitemia at the time of dosing, 64 h after inoculation. Data are means ± SD. Mice were given the vehicle i.p. (n = 8; •), 10 mg/kg PQP i.p. (n = 14; ○), 30 mg/kg DHA i.p. (n = 14; ▵), or a combination of 10 mg/kg PQP plus 30 mg/kg DHA i.p. (n = 14; ▪).