title: Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C(14)-erythromycin breath test and the antipyrine clearance test.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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 10 mg/kg, blood samples were taken for PK, and the clearance (CL(Ant)) was derived. Docetaxel was then given at 75 mg/m(2)/3-weekly or 35 mg/m(2)/weekly. Samples taken for docetaxel PK in first course on day 1 and PK parameters included clearance (CL(Doc)).
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, VIC 8006, Australia. Michael.Michael@petermac.org
authors.forename: M
authors.initials: M
authors.lastname: Michael
authors.forename: C
authors.initials: C
authors.lastname: Cullinane
authors.forename: A
authors.initials: A
authors.lastname: Hatzimihalis
authors.forename: C
authors.initials: C
authors.lastname: O'Kane
authors.forename: A
authors.initials: A
authors.lastname: Milner
authors.forename: R
authors.initials: R
authors.lastname: Booth
authors.forename: S
authors.initials: S
authors.lastname: Schlicht
authors.forename: S J
authors.initials: SJ
authors.lastname: Clarke
authors.forename: P
authors.initials: P
authors.lastname: Francis
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000493:pharmacokinetics; D019540:Area Under Curve; D001944:Breath Tests / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000983:Antipyrine