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Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake
- Source :
- British Journal of Clinical Pharmacology
- Publication Year :
- 2020
- Publisher :
- Wiley, 2020.
-
Abstract
- Aim Regorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M-2 and M-5 in solid tumours. Methods The model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib. This was then applied to sparsely sampled data from four phase 3 studies in patients with advanced solid tumours. The need for exact food intake data to estimate individual drug exposure was evaluated. Results By incorporating EHC, the model adequately described the PK profiles of regorafenib, M-2 and M-5 after single and multiple doses in patients from phase 1 studies. Individual exposure in phase 3 studies was adequately described based on assumptions on the time and frequency of food intake, although exact food intake data are recommended to improve the estimation. Covariate analysis identified sex and body mass index (BMI) as impacting exposure to regorafenib, and sex as strongly impacting exposure to M-2 and M-5 (also influenced by the BMI effect on parent regorafenib in the joint model developed); however, these factors accounted for a small portion of the overall variability in exposure. Conclusions The adequate description of regorafenib PK after multiple dosing requires the incorporation of EHC. Neither single nor combined covariates predicted exposures that would warrant a priori regorafenib dose adjustment.
- Subjects :
- Oncology
Drug
medicine.medical_specialty
Pyridines
media_common.quotation_subject
Population
Antineoplastic Agents
030226 pharmacology & pharmacy
law.invention
Eating
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Pharmacokinetics
population pharmacokinetics
law
Neoplasms
Internal medicine
Regorafenib
Enterohepatic Circulation
medicine
Humans
Pharmacology (medical)
030212 general & internal medicine
education
Enterohepatic circulation
Active metabolite
media_common
Pharmacology
education.field_of_study
Clinical pharmacology
business.industry
Phenylurea Compounds
Original Articles
drug metabolism
chemistry
Original Article
regorafenib
clinical pharmacology
business
Body mass index
Subjects
Details
- ISSN :
- 13652125 and 03065251
- Volume :
- 86
- Database :
- OpenAIRE
- Journal :
- British Journal of Clinical Pharmacology
- Accession number :
- edsair.doi.dedup.....1d2103c08b9cb0ccb6c1b0f624bdf288