Evaluation of CYP3A activity as a predictive covariate for docetaxel clearance

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2006 Background: Docetaxel exhibits wide interindividual variation in drug clearance (CL). Reduction in CL by ≥25% is associated with increased neutropenia. Docetaxel is metabolized by cytochrome P4503A (CYP3A) and pts with liver impairment have reduced CL. The objective of this study was to prospectively evaluate the association between liver function tests (LFTs), CYP3A activity and docetaxel CL. Methods: PK studies were performed during cycle 1 of therapy in 58 cancer pts. Docetaxel was administered once every 3 weeks according to LFT group (gp): (Gp 1) 75 mg/m2, normal LF; (Gp 2) 75 mg/m2, total bilirubin [Tbili] <1.5 x ULN and AST/ALT >1 x ULN with alkaline phosphatase [AP] ≥2.5 x ULN, or AST/ALT ≥1.5 x ULN with AP >1 x ULN, or isolated elevations of AST/ALT or AP ≥5 x ULN; (Gp 3A) 50mg/m2, Tbili <1.5 x ULN and AST/ALT ≥1.5 x ULN with AP ≥2.5 x ULN; and (Gp 3B) 40 mg/m2, Tbili ≥1.5 x ULN with any AST/ALT and/or AP elevations. CL was calculated from compartmental modelling. Pre-treatment CYP3A activity was determined using the erythromycin breath test (ERMBT). Results: CL was lower in pts with more abnormal LFTs (mean [range], 11.0 [6.1 - 23.7] L/h [gp 3] vs 28.7 [9.5 - 92.6] [gp 1–2]; P = .0014). CL was similar yet highly variable in pts in gp 1–2 (P = .75). Log-transformed CYP3A correlated well with docetaxel CL in all pts (R = 0.48; P = .0001). CL was lower in pts with CYP3A values in the lower quartile (<1.7%) (P = .0003) (Table 1); five of 8 (63%) pts with normal LFTs (gp 1) but CYP3A <1.7% had reduced CL by ≥25%. Six of 9 (67%) pts in LFT group 2 with CYP3A ≥1.7% did not have reduced CL ≥25%, although recent manufacturer's dosing guidelines recommend against treating these patients with docetaxel.Conclusions: LF alone does not explain variability in drug CL. These data indicate that CYP3A activity is an additional predictive covariate for drug CL and may deserve consideration as a factor in dose calculation for docetaxel. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Pharmaceuticals Aventis Pharmaceuticals