Dexamethasone as an in vivo probe for CYP3A metabolism: application to docetaxel and vinorelbine

Abstract

2036 Background: Since none endogenous marker is able to predict accurately clearance of metabolised drugs, two separate studies were conducted in order to assess the possibility to use dexamethasone as an in vivo probe for predicting docetaxel and/or vinorelbine clearance. Indeed, dexamethasone, vinorelbine and docetaxel are all mainly metabolised by cytochrome P450 3A4/5 and all are substrate of the ABCB1 transporter. Methods: Patients were receiving docetaxel (21 pts) or vinorelbine (20 pts) as part of established protocols. Dexamethasone (20 mg, iv) was given the day before chemotherapy. Plasma and urinary concentrations of both unchanged dexamethasone and its main metabolite, 6-beta-hydroxydexamethasone, were determined by HPLC Method: Genotyping of both CYP3A5 and ABCB1 have been also performed. The correlation between docetaxel or vinorelbine clearance and dexamethasone pharmacokinetic parameters was assessed using a population pharmacokinetic approach and NONMEM program. Results: A significant correlation between dexamethasone pharmacokinetic parameters and both docetaxel and vinorelbine clearance was found. Covariate models were obtained by considering dexamethasone plasma clearance (DPC) together with other covariates. For docetaxel, best covariate model was: CL (L/hr) = 356. fu. (1 - 0.17 . HPMT) . (1 + 0.126 . DPC) with fu for the unbound plasma fraction of docetaxel estimated from serum alpha 1 acid glycoprotein level, HPMT =1 or =0 if presence of hepatic metastasis or not, and DPC in L/hr. Interindividual variability in CL decreased from 38% (no covariate) to 15% by considering these three covariates. Mean total docetaxel AUC was not significantly larger in patients who experienced severe neutropenia, then the difference was significant (p=0.02) for AUCu (unbound docetaxel plasma exposure) between patients with or without severe toxicity. For vinorelbine, the best covariate model was: CL (L/hr) = 39.8. (DPC/13.2)0.524. (ALP/137)−0.198 with ALP for alkaline phosphatase level (IU). Interindividual variability in CL decreased from 29.7% (no covariate) to 14.7% by considering DPC and ALP. Conclusions: Dexamethasone may be used as a probe for individual dosing of docetaxel and vinorelbine. No significant financial relationships to disclose.