Physiologically based pharmacokinetic modeling (PBPK) to predict drug-drug interactions for encorafenib. Part II. Prospective predictions in hepatic and renal impaired populations with clinical inhibitors and inducers
Creators: name: Kollipara, Sivacharan
name: Ahmed, Tausif
name: Praveen, Sivadasu
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biochemistry
subject: Microbiology
subject: FOS: Biological sciences
subject: Genetics
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Marine Biology
subject: Hematology
subject: Virology

description: Encorafenib, a potent BRAF kinase inhibitor gets significantly metabolised by CYP3A4 (83%) and CYP2C19 (16%) and is a substrate for P-glycoprotein (P-gp). Due to significant metabolism by CYP3A4, encorafenib exposure can increase in hepatic and renal impairment and may lead to altered magnitude of drug-drug interactions (DDI). Hence, it is necessary to assess the exposures &amp; DDI’s in impaired population.Physiologically based pharmacokinetic modelling (PBPK) was utilised to determine the exposures of encorafenib in hepatic and renal impairment along with altered DDI’s. Prospective DDI’s were predicted with USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors and CYP3A4 inducers.PBPK models for encorafenib, perpetrators simulated PK parameters within 2-folds error. Encorafenib exposures significantly increased in hepatic as compared to renal impairment because of reduced CYP3A4 levels.Hepatic impairment caused changes in inhibition and induction DDI’s, when compared to healthy population. Renal impairment did not cause significant changes in DDIs except for itraconazole. P-gp, CYP2C19 inhibitors did not result in altered DDI’s. The DDI’s were found to have insignificant correlation with relative exposure increase of perpetrators in case of impairment. Overall, this work signifies use of PBPK modelling for DDI’s evaluations in hepatic and renal impairment populations. Encorafenib, a potent BRAF kinase inhibitor gets significantly metabolised by CYP3A4 (83%) and CYP2C19 (16%) and is a substrate for P-glycoprotein (P-gp). Due to significant metabolism by CYP3A4, encorafenib exposure can increase in hepatic and renal impairment and may lead to altered magnitude of drug-drug interactions (DDI). Hence, it is necessary to assess the exposures &amp; DDI’s in impaired population. Physiologically based pharmacokinetic modelling (PBPK) was utilised to determine the exposures of encorafenib in hepatic and renal impairment along with altered DDI’s. Prospective DDI’s were predicted with USFDA recommended clinical CYP3A4, CYP2C19, P-gp inhibitors and CYP3A4 inducers. PBPK models for encorafenib, perpetrators simulated PK parameters within 2-folds error. Encorafenib exposures significantly increased in hepatic as compared to renal impairment because of reduced CYP3A4 levels. Hepatic impairment caused changes in inhibition and induction DDI’s, when compared to healthy population. Renal impairment did not cause significant changes in DDIs except for itraconazole. P-gp, CYP2C19 inhibitors did not result in altered DDI’s. The DDI’s were found to have insignificant correlation with relative exposure increase of perpetrators in case of impairment. Overall, this work signifies use of PBPK modelling for DDI’s evaluations in hepatic and renal impairment populations.