Potential Sources of Inter-subject Variability in Monoclonal Antibody Pharmacokinetics

Understanding inter-subject variability in drug pharmacokinetics and pharmacodynamics is important to ensure that all patients attain suitable drug exposure to achieve efficacy and avoid toxicity. Inter-subject variability in the pharmacokinetics of therapeutic monoclonal antibodies (mAbs) is generally moderate to high; however, the factors responsible for the high inter-subject variability have not been comprehensively reviewed. In … Continued

Prediction of Voriconazole Non-linear Pharmacokinetics Using a Pediatric Physiologically-based Pharmacokinetic Modeling Approach

We read with interest the report by Zane and Thakker entitled ‘‘A PBPK model for voriconazole disposition predicts intestinal first-pass metabolism in children’’. We believe the authors should be congratulated for tackling the complex case of voriconazole, as this is a drug with non-linear pharmacokinetics where clinical trials have shown a marked difference between adults … Continued

Population Pharmacokinetics Analysis of Vigabatrin in Adults and Children with Epilepsy and Children with Infantile Spasms

Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration–time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of … Continued

A Re-evaluation and Validation of Ontogeny Functions for CYPs 1A2 and 3A4 Based on In Vivo Data

Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in pediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. We report ontogeny functions for these enzymes as pediatric to adult relative intrinsic … Continued

Anatomical, Physiological and Metabolic Changes with Gestational Age During Normal Pregnancy: A Database for Parameters Required in Physiologically-based Pharmacokinetic Modeling

Pregnancy is associated with considerable changes in the physiological, anatomical and biochemical attributes in women. These may alter the exposure to xenobiotics between pregnant and non-pregnant women who receive similar doses, with implications for different susceptibility to environmental pollutants or therapeutic agents. Physiologically based pharmacokinetic (PBPK) models together with in vitro in vivo extrapolation (IVIVE) … Continued

Differences in Cytochrome P450-mediated Pharmacokinetics Between Chinese and Caucasian Populations Predicted by Mechanistic Physiologically-based Pharmacokinetic Modeling

International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines emphasize the need for better understanding of the influence of ethnicity on drug response to minimize duplication of clinical studies, thereby expediting drug approval. We have developed a Chinese database for the prediction of differences in the population kinetics of drugs mainly metabolized … Continued

A Mechanistic Framework for In Vitro-In Vivo Extrapolation of Liver Membrane Transporters: Prediction of Drug-drug Interaction Between Rosuvastatin and Cyclosporine

The interplay between liver metabolizing enzymes and transporters is a complex process involving system-related parameters such as liver blood perfusion as well as drug attributes including protein and lipid binding, ionization, relative magnitude of passive and active permeation. Metabolism- and/or transporter-mediated drug–drug interactions (mDDIs and tDDIs) add to the complexity of this interplay. Thus, gaining meaningful insight into the impact of each element on … Continued

Characterizing Systemic Exposure of Inhaled Drugs: Application to the Long-acting β2-agonist PF-00610355

PF-00610355 is an orally inhaled long-acting β2-adrenoreceptor agonist that is being developed for the once-daily treatment of chronic obstructive pulmonary disease (COPD). The pharmacological effect is exerted in the lungs. However, systemic exposure of PF-00610355 is expected to be responsible for certain drug-related adverse effects. This analysis characterizes PF-00610355 using an integrated analysis of systemic … Continued

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