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Andrews KA, Owen JS, McCarthy J, et al. Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development. Clin Transl Sci. 2020;14(2):712-719doi: 10.1111/cts.12934.
Andrews, K. A., Owen, J. S., McCarthy, J., Wesche, D., Gobeau, N., Grasela, T. H., & Möhrle, J. J. (2021). Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development. Clinical and translational science, 14(2), 712-719. https://doi.org/10.1111/cts.12934
Andrews, Kayla Ann, et al. "Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development." Clinical and translational science vol. 14,2 (2021): 712-719. doi: https://doi.org/10.1111/cts.12934
Andrews KA, Owen JS, McCarthy J, Wesche D, Gobeau N, Grasela TH, Möhrle JJ. Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development. Clin Transl Sci. 2021 Mar;14(2):712-719. doi: 10.1111/cts.12934. Epub 2020 Dec 16. PMID: 33326705; PMCID: PMC7993277.
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Clin Transl Sci. 2021 Mar;14(2):712-719. doi: 10.1111/cts.12934. Epub 2020 Dec 16.

Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development.

Clinical and translational science

Kayla Ann Andrews, Joel S Owen, James McCarthy, David Wesche, Nathalie Gobeau, Thaddeus H Grasela, Jörg J Möhrle

Affiliations

  1. Cognigen Corporation, a SimulationsPlus Company, Buffalo, New York, USA.
  2. Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, USA.
  3. The Royal Melbourne Hospital, The University of Melbourne at the Doherty Institute, Melbourne, Australia.
  4. Certara Strategic Consulting, Princeton, New Jersey, USA.
  5. Medicines for Malaria Venture, Geneva, Switzerland.

PMID: 33326705 PMCID: PMC7993277 DOI: 10.1111/cts.12934

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.

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