1. Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development.
- Author
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Andrews KA, Owen JS, McCarthy J, Wesche D, Gobeau N, Grasela TH, and Möhrle JJ
- Subjects
- Antimalarials pharmacokinetics, Cohort Studies, Computer Simulation, Dose-Response Relationship, Drug, Healthy Volunteers, Humans, Malaria parasitology, Plasmodium pathogenicity, Research Design, Retrospective Studies, Antimalarials administration & dosage, Clinical Trials, Phase I as Topic, Malaria drug therapy, Models, Biological, Plasmodium drug effects
- Abstract
Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single-dose cohorts, as many as necessary to obtain the dose-response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose-response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive-cohort data for OZ439 (mixing the data of the three single-dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three-compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug-induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single-cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single-cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2021
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