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

Abstract

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.Chloroquine (CQ) was introduced 50 years ago as an alternative to quinine (25,70). It became the drug of choice for both prophylaxis and treatment of malaria, but resistance has caused a decline in the contemporary clinical use of chloroquine (25,35,40,70,72). Nevertheless, CQ remains one of the most important antimalarial drugs, especially in the treatment of vivax malaria and special patient groups, such as children and pregnant women (32,37,48,51,73), not least because it is inexpensive and well tolerated and has a rapid onset of action. Recent studies have clarified the mechanism of CQ resistance and shown that clinical efficacy of CQ may return at least a decade after it has been withdrawn from use, prompting suggestions that CQ could reemerge as an important therapeutic option for malaria, most likely in combination with artemisinin compounds or chemosensitizing agents (25,28,36,42,45,70).Notwithstanding its clinical status, CQ has a prominent role as a comparator for in vitro and in vivo preclinical testing of new antimalarial drugs (54,56,68,74). Remarkably, there is a paucity of pharmacokinetic and pharmacodynamic data for CQ in preclinical animal models, particularly in murine malaria models (4,11,29).The pharmacokinetic parameters for CQ exhibit wide interindividual variation, although limitations in study design and analytical procedures have been contributing factors (18,64,65). Recent clinical stud...

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

“…Our analyses showed that the 95% CI encompassed both 2/3 and 3/4 for CL of artemether and artemisinin, whereas the upper limit of the 95% CIs for mefloquine, quinine, and chloroquine (0.63, based on reanalysis of a previous study [33]) were all Ͻ0.65 (Table 1). In contrast, the allometric exponents for dihydroartemisinin and piperaquine CL were 0.85 and 0.96, respectively, and the 95% CI of the exponent spanned unity.…”

“…Notwithstanding the limitations of interspecies scaling and the power law relationship debate, allometric scaling data indicate that fixed exponents of 2/3 or 3/4 may not be universally applicable in pharmacokinetics (24,28,29,31,33,38,44,47). Our analyses showed that the 95% CI encompassed both 2/3 and 3/4 for CL of artemether and artemisinin, whereas the upper limit of the 95% CIs for mefloquine, quinine, and chloroquine (0.63, based on reanalysis of a previous study [33]) were all Ͻ0.65 (Table 1).…”

“…Increasing interest has been shown in the application of interspecies allometric scaling data to predict pharmacokinetic parameters or drug doses in children (27,29,30). Despite a paucity of reports on antimalarial drugs (31,32), interpolation of allometric scaling of chloroquine supports recommendations from clinical studies for higher chloroquine doses in children (8,9,33).…”

“…Exclusions comprised fixed-dose combinations where data for individual drugs were not readily available (sulfadoxine-pyrimethamine, artemether-lumefantrine, atovaquone-proguanil), drugs for which pharmacokinetic data were available from fewer than three mammalian species (amodiaquine and lumefantrine), and drugs that are contraindicated in children (tetracycline and doxycycline). Chloroquine (33) and doxycycline (41) had been studied previously and were excluded.…”

Early Treatment with Chloroquine Inhibits the Immune Response against<i> Plasmodium yoelii</i> Infection in Mice

“…To assess the effects of CQ on the antimalarial immune response, we utilized a single dose of CQ that was not adequate to cure the infection and used it in Py 17XL-infected DBA2 mice, who can ordinarily clear the infection without exogenous treatment (Moore et al 2011). CQ was given to the mice at six hours p.i.…”