Month: March 2011
A Bottom Up Approach to Predicting the Pharmacokinetics (PK) of Theophylline (THEO) and Its Interaction with Fluvoxamine (FLUV) in Liver Cirrhosis
Casopitant: In Vitro Data and Simcyp Simulation to Predict In Vivo Metabolic Interactions Involving Cytochrome P450 3A4
[1-piperidinecarboxamide,4-(4-acetyl-1-piperazinyl)-N-((1R)-1-(3,5-bis(trifluoromethyl)phenyl)-ethyl)-2-(4-fluoro-2-methylphenyl)-N-methyl-(2R,4S), GW679769] has previously been shown to be a potent and selective antagonist of the human neurokinin-1 receptor, the primary receptor of substance P, both in vitro and in vivo, with good brain penetration properties. On the basis of this mode of action it was evaluated for the prevention of chemotherapy-induced and postoperative nausea and vomiting, and for … Continued
Utility of Intersystem Extrapolation Factors in Early Reaction Phenotyping and the Quantitative Extrapolation of Human Liver Microsomal Intrinsic Clearance Using Recombinant Cytochromes P450
Reaction phenotyping using recombinant human cytochromes P450 (P450) has great utility in early discovery. However, to fully realize the advantages of using recombinant expressed P450s, the extrapolation of data from recombinant systems to human liver microsomes (HLM) is required. In this study, intersystem extrapolation factors (ISEFs) were established for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and … Continued
Resurgence in the Use of Physiologically-based Pharmacokinetic Models in Pediatric Clinical Pharmacology: Parallel Shift in Incorporating the Knowledge of Biological Elements and Increased Applicability to Drug Development and Clinical Practice
This study had two primary aims: (i) To describe an example of the development work required for building a ‘pediatric physiologically based pharmacokinetic’ (P-PBPK) model (Simcyp Pediatric ADME Simulator®), (ii) to replicate pediatric clinical studies and undertake theoretical studies to show the potential applications of mechanistic PBPK in pediatric drug clinical investigation and practice, with … Continued
Modeling and Predicting Drug Pharmacokinetics in Patients with Renal Impairment
Current guidance issued by the US FDA to assess the impact of renal impairment on the pharmacokinetics of a drug under development has recently been updated to include evaluation of drugs with non-renal elimination routes. Renal impairment not only affects elimination of the drug in the kidney, but also the non-renal route of drugs that … Continued
Rethinking 3D-QSAR
The average error of pIC50 prediction reported for 140 structures in make-and-test applications of topomer CoMFA by four discovery organizations is 0.5. This remarkable accuracy can be understood to result from a topomer pose’s goal of generating field differences only at lattice intersections adjacent to intended structural change.
