Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C14-erythromycin breath test and the antipyrine clearance test

Abstract

Docetaxel has marked inter-patient PK variability, and metabolic phenotypic probes may enable individualised dosing. This is the first report directly comparing the erythromycin breath test (EBT) (a CYP3A4 probe) with the antipyrine clearance test (ACT), (a general CYP-P450/predominant CYP3A4 probe) for the correlation with docetaxel PK and toxicity. Patients pretherapy underwent: (A) EBT: IV C(14)[N-methyl]-erythromycin was administered and breath samples analysed for (14)CO(2), derived parameters included (1) (14)CO(2) flux at 10-min (CO(2)f(10)), (2) 20-min (CO(2)f(20)), (3) terminal rate constant k(CO2) and (4) AUC(CO2,(0-∞)) and AUC(CO2,(0-60).) (B) ACL test: patients were given oral antipyrine 10mg/kg, blood samples were taken for PK, and the clearance (CL(Ant)) was derived. Docetaxel was then given at 75mg/m(2)/3-weekly or 35mg/m(2)/weekly. Samples taken for docetaxel PK in first course on day 1 and PK parameters included clearance (CL(Doc)). Twenty patients accrued, docetaxel: 3-weekly/weekly=13:7. EBT parameters (N=19) (mean, [CV%]): CO(2)f(10) (%/min) 0.051 (106), CO(2)f(20) 0.052 (82), k(CO2) (min(-1)) 0.007 (22), AUC(CO2,(0-∞)) 7.9 (85), AUC(CO2,(0-60)) 2.64 (81). CL(Ant) (N=19) (ml/min); 35.8 (37). Docetaxel PK parameters (N=19): CL(Doc) (l/h)=57.2 (36), t(Doc1/2) (h)=12.7 (33). No correlations were observed between the docetaxel PK and EBT parameters. For docetaxel weekly patients, a significant linear relationship was observed between CL(Doc) and CL(Ant) (P=0.007, R (2)=79.47%). The utility of EBT for the prediction of docetaxel PK was not confirmed in this study. The antipyrine clearance test may be superior in this regard for docetaxel, but regimen dependent and hence warrants further evaluation.