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Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development.
- Source :
-
Clinical and translational science [Clin Transl Sci] 2021 Mar; Vol. 14 (2), pp. 712-719. Date of Electronic Publication: 2020 Dec 16. - Publication Year :
- 2021
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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.<br /> (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8062
- Volume :
- 14
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Clinical and translational science
- Publication Type :
- Academic Journal
- Accession number :
- 33326705
- Full Text :
- https://doi.org/10.1111/cts.12934