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Population Pharmacokinetics of Selumetinib and Its Metabolite N-desmethyl-selumetinib in Adult Patients With Advanced Solid Tumors and Children With Low-Grade Gliomas
- Source :
- CPT: Pharmacometrics & Systems Pharmacology. 6:305-314
- Publication Year :
- 2017
- Publisher :
- Wiley, 2017.
-
Abstract
- Selumetinib (AZD6244, ARRY-142886), a mitogen activated protein kinases (MEK1 and 2) inhibitor, has been granted orphan drug designation for differentiated thyroid cancer. The primary aim of this analysis was to characterize the population pharmacokinetics of selumetinib and its active metabolite N-desmethyl-selumetinib in patients with cancer. Concentration-time data from adult and pediatric clinical trials were pooled to develop a population pharmacokinetic model using a sequential approach where selumetinib and N-desmethyl-selumetinib data were modeled separately. A sequential zero- and first-order absorption with lag time with a two-compartment model for selumetinib and a two-compartment model for N-desmethyl-selumetinib best described the concentration-time data. Intrapatient variability in absorption was higher than interpatient variability. The apparent drug clearance (CL/F) from the central compartment was 13.5 L/hr (RSE 4.9%). Significant covariates for CL/F were age, alanine aminotransferase, and body surface area. This study confirms that flat dosing is appropriate in adults, whereas body-surface area based dosing should be used in pediatric patients.
- Subjects :
- Body surface area
education.field_of_study
business.industry
Metabolite
Population
Cancer
Pharmacology
medicine.disease
030226 pharmacology & pharmacy
Crossover study
3. Good health
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pharmacokinetics
chemistry
030220 oncology & carcinogenesis
Modeling and Simulation
Selumetinib
medicine
Pharmacology (medical)
education
business
Active metabolite
Subjects
Details
- ISSN :
- 21638306
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- CPT: Pharmacometrics & Systems Pharmacology
- Accession number :
- edsair.doi...........c3e6681f88fe87b1d871eadd88bba680
- Full Text :
- https://doi.org/10.1002/psp4.12175