Browsing by Author "Lewis, Lionel D."

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    Clinical Trial Simulation to Evaluate Population Pharmacokinetics and Food Effect: Capturing Abiraterone and Nilotinib Exposures
    (John Wiley & Sons, Inc., 2015-05) Li, Claire H.; Sherer, Eric A.; Lewis, Lionel D.; Bies, Robert R.; Department of Medicine, IU School of Medicine
    The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different level of between-occasion variability, number of patients in the trial and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures,covariate and variability effects.
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    The relationship of polymorphisms in ABCC2 and SLCO1B3 with docetaxel pharmacokinetics and neutropenia: CALGB 60805 (Alliance)
    (Wolters Kluwer, 2013) Lewis, Lionel D.; Miller, Antonius A.; Owzar, Kouros; Bies, Robert R.; Markova, Svetlana; Jiang, Chen; Kroetz, Deanna L.; Egorin, Merrill J.; McLeod, Howard L.; Ratain, Mark J.; Alliance for Clinical Trials in Oncology; Medicine, School of Medicine
    Docetaxel-related neutropenia was associated with polymorphisms in the drug transporters ABCC2 and SLCO1B3 in Japanese cancer patients. We hypothesized that this association is because of reduced docetaxel clearance, associated with polymorphisms in those genes. We studied 64 US cancer patients who received a single cycle of 75 mg/m of docetaxel monotherapy. We found that the ABCC2 polymorphism at rs-12762549 trended to show a relationship with reduced docetaxel clearance (P=0.048), but not with neutropenia. There was no significant association of the SLCO1B3 polymorphisms with docetaxel clearance or neutropenia. We conclude that the relationship between docetaxel-associated neutropenia and polymorphisms in drug transporters identified in Japanese patients was not confirmed in this cohort of US cancer patients.