Effect of ciprofloxacin on the systemic exposure to erlotinib

Abstract

19047 Background: Erlotinib is a potent oral tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) and has been shown to increase overall survival and PFS in non-small cell lung cancer (NSCLC) and pancreatic cancer. Erlotinib is metabolized primarily by CYP3A4, and to a lesser extent by CYP1A2 and the pulmonary isoform CYP1A1. Although DDI studies have been conducted with CYP3A4 inhibitors, the interaction potential with ciprofloxacin, a quinolone antibiotic which inhibits both CYP3A4 and CYP1A2, has not yet been investigated. Therefore a phase I study was conducted to assess the effect of ciprofloxacin on the pharmacokinetics (PK) of erlotinib. Methods: Single-centre, open-label, one-sequence, two-period cross-over study in male and female healthy volunteers. Subjects received a single dose of 100 mg erlotinib po on Day 1, and 750 mg ciprofloxacin bid for 6 days (Day 13–18) plus a single dose of 100 mg erlotinib po on Day 15. Adverse events, physical examinations, clinical laboratory tests, vital signs, ECG and PK were assessed. Results: 28 subjects (age 19–53 years) were enrolled from May-Aug 2006. Erlotinib was well tolerated alone and together with ciprofloxacin. No deaths, SAEs or withdrawals due to AEs occurred. Erlotinib was absorbed with a median tmax of 3–3.5 h. Plasma concentrations of erlotinib increased when given with ciprofloxacin. The exposure to erlotinib (AUC0-∞) was 10300 ± 4020 ng.h/mL (mean ± SD) when given as single agent vs. 14000 ± 4890 ng.h/mL after concomitant ciprofloxacin administration. The corresponding maximum plasma concentration (Cmax) was 576 ± 312 ng/mL and 617 ± 215 ng/mL, respectively. The geometric mean ratio (90% CI) of erlotinib vs. erlotinib plus ciprofloxacin was 1.39 (1.24, 1.56) for AUC0-∞ and 1.17 (0.98, 1.40) for Cmax. For the active metabolite OSI-420, the mean ratio was 1.62 (1.40, 1.87) for AUC0-last and 1.48 (1.20, 1.82) for Cmax. Conclusions: The systemic exposure to erlotinib and its metabolite increases when erlotinib is co-administered with the CYP3A4/CYP1A2 inhibitor ciprofloxacin. Considering the interpatient variability this might not be clinically relevant. However, caution should be used and dose reduction considered when erlotinib is given together with potent CYP3A4/CYP1A2 inhibitors. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Hoffmann-La Roche