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 … Continued

Application of PBPK Modeling 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 … Continued

Sources of Interindividual Variability in IVIVE of Clearance: An Investigation into the Prediction of Benzodiazepine Clearance Using a Mechanistic Population-based Pharmacokinetic Model

Prediction of metabolic clearance in extreme individuals rather than the ‘average human’ is becoming an attractive tool within the pharmaceutical industry. The current study involved prediction of variability in metabolic clearance for alprazolam, triazolam and midazolam with emphasis on the following factors: first, evaluation of clearance prediction accuracy using intrinsic clearance (CLint) data from in … Continued

Pre-clinical Assessment of the Absorption, Distribution, Metabolism, and Excretion of GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide), an Orally Bioavailable Systemic Hedgehog Signaling Pathway Inhibitor

GDC-0449 (2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide) is a potent, selective Hedgehog (Hh) signalling pathway inhibitor being developed for the treatment of various cancers. The in vivo clearance of GDC-0449 was estimated to be 23.0, 4.65, 0.338, and 19.3 ml min-1 kg-1 in mouse, rat, dog and monkeys, respectively. The volume of distribution ranged from 0.490 in rats to 1.68 … Continued

Prediction of Phase 1 Single-dose Pharmacokinetics Using Recombinant Cytochromes P450 and Physiologically-based Modeling

1. Ten compounds from the Merck Research Laboratories pipeline were selected to evaluate the utility of using intrinsic clearance derived from recombinantly expressed cytochromes P450 (CYP) and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics using simCYP®. The compounds selected were anticipated to be eliminated predominantly by P450 metabolism. 2. There was a reasonable agreement between the predicted and actual clinical exposure with 80% of the predicted exposures … Continued

Utilization of Estimated Physicochemical Properties as an Integrated Part of Predicting Hepatic Clearance in the Early Drug-discovery Stage: Impact of Plasma and Microsomal Binding

Rapid prediction of hepatic clearance for drug candidates plays an important role for decision-making in the early drug-discovery stage. Although knowledge of protein binding in both plasma and microsomal components is needed in the prediction of metabolic clearance from metabolic stability studies, the capacity of protein binding assays are generally lower than those of metabolic … Continued

Comparison of Different Approaches to Predict Metabolic Drug-drug Interactions

Three approaches were compared to predict the actual magnitude of drug interaction (the mean fold-change in the area under the curve (AUC)) of reversible or irreversible (mechanism-based) cytochrome P450 (CYP) inhibitors. These were: (1) the pragmatic use of the ‘[I]/KI‘ approach; (2) the ‘Mechanistic-Static Model’ (MSM), which is a more complex extension of the ‘[I]/KI‘ approach that incorporates f(m,CYP), … Continued

Prediction of In Vivo Drug Clearance from In Vitro Data, I: Impact of Inter-individual Variability

The Simcyp® Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data. Fifteen drugs satisfied the entry criteria for the study and the relevant information (in vitro metabolism data and in vivo human clearance values) were collated from the literature. Predicted values of median clearances fell within … Continued

Prediction of In Vivo Drug Clearance from In Vitro Data, II: Potential Inter-ethnic Differences

Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in … Continued

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