Pharmacokinetics, pharmacodynamics, and allometric scaling of chloroquine in a murine malaria model.

Chloroquine (CQ) is an important antimalarial drug for the treatment of special patient groups and as a comparator for preclinical testing of new drugs. Pharmacokinetic data for CQ in animal models are limited; thus, we conducted a three-part investigation, comprising (i) pharmacodynamic studies of CQ and CQ plus dihydroartemisinin (DHA) in Plasmodium berghei-infected mice, (ii) pharmacokinetic studies of CQ in healthy and malaria-infected mice, and (iii) interspecies allometric scaling for CQ from 6 animal and 12 human studies. The single-dose pharmacodynamic study (10 to 50 mg CQ/kg of body weight) showed dose-related reduction in parasitemia (5- to >500-fold) and a nadir 2 days after the dose. Multiple-dose regimens (total dose, 50 mg/kg CQ) demonstrated a lower nadir and longer survival time than did the same single dose. The CQ-DHA combination provided an additive effect compared to each drug alone. The elimination half-life (t(1/2)), clearance (CL), and volume of distribution (V) of CQ were 46.6 h, 9.9 liters/h/kg, and 667 liters/kg, respectively, in healthy mice and 99.3 h, 7.9 liters/h/kg, and 1,122 liters/kg, respectively, in malaria-infected mice. The allometric equations for CQ in healthy mammals (CL = 3.86 × W(0.56), V = 230 × W(0.94), and t(1/2) = 123 × W(0.2)) were similar to those for malaria-infected groups. CQ showed a delayed dose-response relationship in the murine malaria model and additive efficacy when combined with DHA. The biphasic pharmacokinetic profiles of CQ are similar across mammalian species, and scaling of specific parameters is plausible for preclinical investigations.

Piperaquine pharmacodynamics and parasite viability in a murine malaria model.

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.

Pharmacokinetics and pharmacodynamics of piperaquine in a murine malaria model.

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.

Plasmodium berghei: parasite clearance after treatment with dihydroartemisinin in an asplenic murine malaria model.

Clinical reports indicate that malaria-infected asplenic patients have a reduced capacity for parasite clearance despite intensive antimalarial therapy. The aim of this study was to evaluate the efficacy of dihydroartemisinin in an asplenic murine malaria model. Mice were inoculated with Plasmodium berghei parasitised erythrocytes and received a single dose of dihydroartemisinin 56 h later, at 2-5% parasitaemia. Haematology, liver biochemistry and histopathology of key organs were performed to evaluate organ response to malaria infection. The nadir parasitaemia occurred 20 h after dihydroartemisinin administration, falling 2.8- to 6.0-fold and 2.7- to 6.9-fold in asplenic and intact mice, respectively, (10-100 mg/kg). Histopathology indicated increased stimulation of liver function/activity during malaria infection of asplenic mice (as compared to intact mice). Overall efficacy of single-dose dihydroartemisinin treatment in asplenic mice was similar to intact mice although the rate of recrudescence in asplenic mice was significantly greater than intact mice at 30 and 100 mg/kg. The asplenic murine malaria model could be used in pre-clinical studies of splenic function and clearance of malaria parasites, pathophysiological studies or antimalarial drug efficacy in asplenia.