A Mechanism-Based Population Pharmacokinetic Model for Characterizing Time-Dependent Pharmacokinetics of Midostaurin and its Metabolites in Human Subjects
- 1 January 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Clinical Pharmacokinetics
- Vol. 47 (12), 807-816
- https://doi.org/10.2165/0003088-200847120-00005
Abstract
Background and objective: Midostaurin, a novel potent inhibitor of protein kinase C enzyme and class III receptor tyrosine kinases, including Fms-like tyrosine kinase-3 (FLT3) and c-KIT, shows time-dependent pharmacokinetics in human subjects, presumably due to enzyme auto-induction. The purpose of this study was to develop a mechanism-based population pharmacokinetic model to describe the plasma concentration profiles of midostaurin and its metabolites and to characterize the time course of auto-induction. Subjects and methods: Data from 37 diabetic patients who received oral doses of midostaurin (25 mg twice daily, 50 mg twice daily or 75 mg twice daily) for 28 days were analysed using nonlinear mixed-effects modelling. The structural model included a gut compartment for drug input and central and peripheral compartments for midostaurin, with drug output from the central compartment to either of two compartments for the midostaurin metabolites CGP62221 and CGP52421. Different enzyme induction sub-models were evaluated to account for the observed time-dependent decrease in midostaurin concentrations. Results: An enzyme turnover model, with CGP62221 formation (CL1) being a linear process but CGP52421 formation (CL2) being inducible, was found to be most appropriate. In the pre-induced state, CL1 and CL2 of midostaurin were determined to be 1.47 L/h and 0.501 L/h, respectively. At the end of 28 days of dosing, CL2 was increased by 5.2-, 6.6- and 6.9-fold in the 25 mg, 50 mg and 75 mg groups, respectively, resulting in a 2.1- to 2.5-fold increase in total clearance of midostaurin. The final model estimated a mean maximum fold of induction (Emax) of 8.61 and a concentration producing 50% of the Emax (EC50) of 1700 ng/mL (∼2.9 μmol/L) for CGP52421-mediated enzyme induction. Conclusions: The population pharmacokinetic model that was developed was able to describe the time-dependent pharmacokinetic profiles of midostaurin and its auto-induction mechanism. Thus it may be useful for designing an appropriate dosage regimen for midostaurin. The unique feature of this model included a precursor compartment that was able to capture the time delays of auto-induction. The use of such precursor extension in the model may be applicable to other drugs showing long time delays in enzyme auto-induction.Keywords
This publication has 26 references indexed in Scilit:
- Retrospective analysis of artemisinin pharmacokinetics: application of a semiphysiological autoinduction modelBritish Journal of Clinical Pharmacology, 2006
- Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412Published by American Society of Hematology ,2005
- Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectivesDiabetes/Metabolism Research and Reviews, 2003
- The Kinase Inhibitor PKC412 Suppresses Epiretinal Membrane Formation and Retinal Detachment in Mice with Proliferative RetinopathiesInvestigative Ophthalmology & Visual Science, 2003
- A mechanism‐based pharmacokinetic‐enzyme model for cyclophosphamide autoinduction in breast cancer patientsBritish Journal of Clinical Pharmacology, 1999
- Population pharmacokinetics of methadone in opiate users: characterization of time‐dependent changesBritish Journal of Clinical Pharmacology, 1999
- Dramatic Inhibition of Retinal and Choroidal Neovascularization by Oral Administration of a Kinase InhibitorThe American Journal of Pathology, 1999
- The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions.JCI Insight, 1998
- Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring dataBritish Journal of Clinical Pharmacology, 1997
- A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and In vitro anti‐proliferative as well as In vivo anti‐tumor activityInternational Journal of Cancer, 1989