Physiologically Based Pharmacokinetic Models for Adults and Children Reveal a Role of Intracellular Tubulin Binding in Vincristine Disposition
| Autor: | Gareth J. Veal, Nicole R. Zane, Christine M. Lee, Dhiren R. Thakker |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Vincristine Physiologically based pharmacokinetic modelling Pharmacology Models Biological Article Tubulin binding Cell Line Young Adult Dogs Pharmacokinetics Tubulin medicine Animals Cytochrome P-450 CYP3A Humans Pharmacology (medical) Child Volume of distribution CYP3A4 Chemistry Research lcsh:RM1-950 Area under the curve Infant Newborn Infant Articles Middle Aged Antineoplastic Agents Phytogenic lcsh:Therapeutics. Pharmacology Modeling and Simulation Area Under Curve Child Preschool Administration Intravenous Efflux medicine.drug |
| Zdroj: | CPT: Pharmacometrics & Systems Pharmacology, Vol 8, Iss 10, Pp 759-768 (2019) CPT: Pharmacometrics & Systems Pharmacology |
| ISSN: | 2163-8306 |
| Popis: | Vincristine is a cytotoxic chemotherapeutic agent used as first-line therapy for pediatric acute lymphocytic leukemia. It is cleared by hepatic oxidative metabolism by CYP3A4 and CYP3A5 and via hepatic (biliary) efflux mediated by P-glycoprotein (P-gp) transporter. Bottom-up physiologically based pharmacokinetic (PBPK) models were developed to predict vincristine disposition in pediatric and adult populations. The models incorporated physicochemical properties, metabolism by CYP3A4/5, efflux by P-gp, and intracellular binding to β-tubulin. The adult and pediatric PBPK models predicted pharmacokinetics (PK) within twofold of the observed PK parameters (area under the curve, terminal half-life, volume of distribution, and clearance). Simulating a higher hypothetical (4.9-fold) pediatric expression of β-tubulin relative to adult improved predictions of vincristine PKs. To our knowledge, this is the first time that intracellular binding has been incorporated into a pediatric PBPK model. Utilizing this PBPK modeling approach, safe and effective doses of vincristine could be predicted. |
| Databáze: | OpenAIRE |
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