Application of PBPK modelling in drug discovery and development at Pfizer.

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the […]

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Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.

Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. This study shows that adjustment of fesoterodine dose is not warranted when […]

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Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction

Cytochrome P450 3A4 (CYP3A4) is the most important enzyme in drug metabolism and because it is the most frequent target for pharmacokineticdrug-drug interactions (DDIs) it is highly desirable to be able to predict CYP3A4-based DDIs from in vitro data. In this study, the prediction of clinicalDDIs for 30 drugs on the pharmacokinetics of midazolam, a probe substrate for CYP3A4, was done using in vitro inhibition, […]

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Maraviroc: in vitro assessment of drug-drug interaction potential.

AIMS: To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug-drug interactions (DDIs). METHODS: Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. […]

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Application of CYP3A4 in vitro data to predict clinical drug-drug interactions: predictions of compounds as objects of interaction.

Numerous retrospective analyses have shown the utility of in vitro systems for predicting potential drug-drug interactions (DDIs). Prediction of DDIs from in vitro data is commonly obtained using estimates of enzyme KI, inhibitor and substrate concentrations and absorption rate for substrate and inhibitor. Using a generic approach for all test compounds, the findings from the current study showed the use of recombinant P450s provide […]

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Case studies addressing human pharmacokinetic uncertainty using a combination of pharmacokinetic simulation and alternative first in human

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min-1  kg-1 for PF-184298, and 5 to >20 mL min-1 […]

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