The effect of itraconazole and rifampicin on the pharmacokinetics of osimertinib
Journal
British Journal of Clinical Pharmacology
Journal Volume
84
Journal Issue
6
Pages
1156-1169
Date Issued
2018
Author(s)
Vishwanathan K
Dickinson P.A
So K
Thomas K
Chen Y.-M
De Castro Carpeño J
Dingemans A.-M.C
Kim H.R
Kim J.-H
Krebs M.G
Bui K
Weilert D
Harvey R.D.
Abstract
Aims: We investigated the effects of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampicin) on the pharmacokinetics of the epidermal growth factor receptor-tyrosine kinase inhibitor osimertinib, in patients with advanced non-small cell lung cancer in two Phase I, open-label, two-part clinical studies. Part one of both studies is reported. Methods: In the itraconazole study (NCT02157883), patients received single-dose osimertinib 80?mg on Days 1 and 10 and itraconazole (200?mg twice daily) on Days 6–18 orally. In the rifampicin study (NCT02197247), patients received osimertinib 80?mg once daily on Days 1–77 and rifampicin 600?mg once daily on Days 29–49. Results: In the itraconazole study (n?=?36), the geometric least squares mean (GMLSM) ratios (osimertinib plus itraconazole/osimertinib alone) for C max and AUC were 80% (90% CI 73, 87) and 124% (90% CI 115, 135), respectively, below the predefined no-effect upper limit of 200%. In the rifampicin study (n?=?40), the GMLSM ratios (osimertinib plus rifampicin/osimertinib alone) for C ss,max and AUCτ were 27% (90% CI 24, 30) and 22% (90% CI 20, 24), respectively, below the predefined no-effect lower limit of 50%. The induction effect of rifampicin was apparent within 7 days of initiation; osimertinib C ss,max and AUCτ values returned to pre-rifampicin levels within 3 weeks of rifampicin discontinuation. No new osimertinib safety findings were observed. Conclusions: Osimertinib can be co-administered with CYP3A4 inhibitors, but strong CYP3A inducers should be avoided if possible. ? 2018 The British Pharmacological Society
Subjects
clinical pharmacology, drug metabolism; drug analysis, lung cancer; drug information; drug interactions; oncology; pharmacokinetics, biomarkers
SDGs
Other Subjects
itraconazole; osimertinib; rifampicin; antineoplastic agent; cytochrome P450 3A inducer; cytochrome P450 3A inhibitor; itraconazole; osimertinib; piperazine derivative; protein kinase inhibitor; rifampicin; adult; advanced cancer; aged; analytic method; area under the curve ratio; Article; cancer combination chemotherapy; clinical article; diarrhea; drug blood level; drug clearance; drug effect; drug half life; drug metabolism; drug safety; drug tolerability; drug withdrawal; dry skin; fatigue; female; femur fracture; heart failure; human; hyperkalemia; influenza; lobar pneumonia; malaise; male; maximum concentration; muscle weakness; nausea; non small cell lung cancer; open study; pharmacokinetic parameters; phase 1 clinical trial; priority journal; respiratory syncytial virus infection; single drug dose; steady state; stomatitis; thrombophlebitis; time to maximum plasma concentration; very elderly; vomiting; biological model; clinical trial; drug administration; drug interaction; lung tumor; middle aged; non small cell lung cancer; oral drug administration; pathology; risk assessment; risk factor; treatment outcome; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Drug Administration Schedule; Drug Interactions; Female; Humans; Itraconazole; Lung Neoplasms; Male; Middle Aged; Models, Biological; Piperazines; Protein Kinase Inhibitors; Rifampin; Risk Assessment; Risk Factors; Treatment Outcome
Publisher
Blackwell Publishing Ltd
Type
journal article