Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development
| Autor: | James S. McCarthy, Kayla Ann Andrews, Nathalie Gobeau, Joel S. Owen, Thaddeus H. Grasela, David Wesche, Jörg J. Möhrle |
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| Rok vydání: | 2020 |
| Předmět: |
Oncology
Complete data medicine.medical_specialty Plasmodium Gompertz function Models Biological General Biochemistry Genetics and Molecular Biology Article Cohort Studies Antimalarials Pharmacokinetics Internal medicine medicine Retrospective analysis Humans Computer Simulation General Pharmacology Toxicology and Pharmaceutics Volunteer Retrospective Studies Clinical Trials Phase I as Topic Dose-Response Relationship Drug Pharmacokinetic pharmacodynamic business.industry lcsh:Public aspects of medicine General Neuroscience Research lcsh:RM1-950 lcsh:RA1-1270 General Medicine Articles Healthy Volunteers Malaria lcsh:Therapeutics. Pharmacology Drug development Research Design Pharmacodynamics business |
| Zdroj: | Clinical and Translational Science Clinical and Translational Science, Vol 14, Iss 2, Pp 712-719 (2021) |
| ISSN: | 1752-8062 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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