title: Pharmacokinetic and pharmacodynamic considerations in antimalarial dose optimization.
abstract: Antimalarial drugs have usually been first deployed in areas of malaria endemicity at doses which were too low, particularly for high-risk groups such as young children and pregnant women. This may accelerate the emergence and spread of resistance, thereby shortening the useful life of the drug, but it is an inevitable consequence of the current imprecise method of dose finding. An alternative approach to dose finding is suggested in which phase 2 studies concentrate initially on pharmacokinetic-pharmacodynamic (PK-PD) characterization and in vivo calibration of in vitro susceptibility information. PD assessment is facilitated in malaria because serial parasite densities are readily assessed by microscopy, and at low densities by quantitative PCR, so that initial therapeutic responses can be quantitated accurately. If the in vivo MIC could be characterized early in phase 2 studies, it would provide a sound basis for the choice of dose in all target populations in subsequent combination treatments. Population PK assessments in phase 2b and phase 3 studies which characterize PK differences between different age groups, clinical disease states, and human populations can then be combined with the PK-PD observations to provide a sound evidence base for dose recommendations in different target groups.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandCentre for Tropical Medicine, Churchill Hospital, Oxford University, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
mesh_terms: D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology; D002648:Child; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D016903:Drug Monitoring; D004351:Drug Resistance; D005260:Female; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011247:Pregnancy
chemical_list: D000962:Antimalarials