Docetaxel clearance is non linear and not predicted by CYP3A phenotyping when administered with ketoconazole

Abstract

2058 Background: Previously we reported that CYP3A phenotyping with midazolam could predict interindividual docetaxel pharmacokinetic variability (J Clin Oncol 2002;20:3683). We hypothesized that strong inhibition of CYP3A activity could reduce interindividual variability of docetaxel leading to more uniform pharmacokinetics (PK), and that CYP3A phenotyping could predict this inhibition. Methods: A dose escalation study was conducted using intravenous docetaxel over 1 hour q3w in combination with ketoconazole 2 days before and after docetaxel. Intravenous midazolam PK using a dose of 1 mg was also studied in these patients. Results: Twenty patients with tumors refractory to standard chemotherapy were enrolled at docetaxel doses of 10 (1 pt), 20 (6 pts), 25 (6 pts), 30 (5 pts) mg/m2; 2 were non evaluable. Median age, Karnofsky performance status and no. of previous chemotherapy regimens were 62 years (34–77), 90% and 2 respectively. Dose-limiting toxicities were observed at 20 (fatigue), 25 (neutropenic fever), and 30 mg/m2 (fatigue). Docetaxel clearance showed surprisingly increased variability with ketoconazole across and within dose levels, and increased significantly with dose (r= 0.54, p =0.02). Clearance was 4.4 ± 3.2, 9.6 ± 4.2 and 22.7 ± 7 L/h/m2.at doses of 20, 25, 30 mg/m2, respectively. Midazolam clearance was 62.3 ± 30.4 mL/min, which is 7-fold slower with ketoconazole compared to our previous data, and did not correlate with docetaxel clearance. Body-surface area did not correlate with the clearance of docetaxel (r = 0.06, p = 0.82). Conclusions: In vivo inhibition of CYP3A does not affect midazolam and docetaxel equally, and does not reduce variability of docetaxel PK. Docetaxel clearance in the presence of CYP3A inhibition is nonlinear, suggesting activation of alternate metabolic pathways or routes of clearance. Treatment at fixed docetaxel doses of 50 and 60 mg is planned. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration National Health Group, Singapore