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Title: Assessment of algorithms for the prediction of metabolic drug-drug interactions
Author: Guest, Eleanor
ISNI:       0000 0004 2715 7681
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2011
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The aim of this work was to assess the ability of the static and dynamic (incorporating the time-course of the inhibitor) prediction models to predict drug-drug interactions (DDIs) using a population-based ADME simulator (Simcyp). This analysis focused on fluconazole, ketoconazole, itraconazole, fluoxetine and fluvoxamine, as CYP inhibitors. The rationale for their selection was an abundance of reported DDI studies, involving a wide range of victim drugs. Preliminary analysis focused on the individual victim drug and inhibitor parameters that are utilised in the DDI prediction models. The victim drug properties included in the DDI prediction models are calculated intrinsically in the Simcyp simulator from in vitro data; these values were compared to estimates obtained by different in vivo methods. Estimations of the fraction metabolised by CYP enzymes were generally consistent with <20% difference between all methods for 15/23 victim drugs. No relationship was observed per CYP enzyme or per inhibitor utilised for phenocopying methods. Estimates of fraction of drug escaping metabolism in the gut were variable across methods with up to 60% coefficient of variation in the case of saquinavir. In vitro assessment of potential liver uptake of the inhibitors was identified for further investigation due to inconsistency in available literature data and sensitivity of the model to this parameter. Extent of liver uptake of selected inhibitors was assessed via comparison of clearance obtained in hepatocytes and microsomes (conventional depletion assay) and values obtained by the conventional depletion and media loss assays in hepatocytes. Clearance was determined at a low concentration (0.1μM) and both rat and human hepatocytes and microsomes were used. The clearance ratios ranged from no difference to >1500 (fluvoxamine from the media loss assay in human hepatocytes). No consistency was observed between methods and human or rat source for any of the inhibitors investigated; therefore, the inclusion of liver uptake into the prediction of DDIs for the current inhibitors was not supported. A database was collated from literature reports of DDIs involving the above named CYP inhibitors (n=97) and used to assess the inclusion of the time-course of inhibition into DDI prediction using the Simcyp simulator. In addition, the impact of active metabolites, dosing time and the ability to predict inter-individual variability in DDI magnitude were investigated using the dynamic prediction model. Simulations comprised of 10 trials with matching population demographics and dosage regimen to the in vivo studies. The predictive utility of the static and dynamic models was assessed relative to the inhibitor or victim drug investigated; both models were employed within Simcyp for consistency in parameters. Use of the dynamic and static models resulted in comparable prediction success, with 67 and 70% of DDIs predicted within two-fold, respectively. Over 60% of strong DDIs (>five-fold AUC increase) were under-predicted by both models, particularly for fluoxetine and fluvoxamine. Incorporation of the itraconazole metabolite into the dynamic model resulted in increased prediction accuracy of strong DDIs (80% within two-fold); no difference was observed for the inclusion of the fluoxetine metabolite. Predicted inter-individual variability in the DDI magnitude was also assessed in healthy, patient and genotyped subjects using a subset of clinical interactions (n=24). Mixed prediction success was observed and the importance of reliable clinical data was highlighted. The differences observed with the dose staggering and the incorporation of active metabolite highlight the importance of these variables in DDI prediction. Finally, the traditional 'two-fold limits' as a measure of the prediction success were reassessed, in particular at AUC ratios approaching one. New limits proposed are applicable for both inhibition and induction DDIs and allow incorporation of the variability in pharmacokinetics of the victim drug when required. DDI predictions were refined using in vitro clearance data for the inhibitors, and assessed using the new predictive measure.
Supervisor: Galetin, Aleksandra ; Houston, James Sponsor: Simcyp Ltd
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available