Pharmacokinetics, Pharmacodynamics, and Allometric Scaling of Chloroquine in a Murine Malaria Model
| Autor: | Brioni R. Moore, Madhu Page-Sharp, Jeffrey D. Jago, Kenneth F. Ilett, Kevin T. Batty, Jillian R. Stoney |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Plasmodium berghei medicine.medical_treatment Dihydroartemisinin Parasitemia Pharmacology Antimalarials Mice Pharmacokinetics Chloroquine parasitic diseases medicine Animals Pharmacology (medical) Chromatography High Pressure Liquid Volume of distribution Mice Inbred BALB C Dose-Response Relationship Drug biology business.industry medicine.disease biology.organism_classification Artemisinins Malaria Disease Models Animal Dose–response relationship Infectious Diseases Pharmacodynamics Drug Therapy Combination business medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 55:3899-3907 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.00067-11 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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