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

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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 C14[N-methyl]-erythromycin was administered and breath samples analysed for 14CO2, derived parameters included (1) 14CO2 flux at 10-min (CO2f10), (2) 20-min (CO2f20), (3) terminal rate constant kCO2 and (4) AUCCO2,(0–∞) and AUCCO2,(0–60). (B) ACL test: patients were given oral antipyrine 10 mg/kg, blood samples were taken for PK, and the clearance (CLAnt) was derived. Docetaxel was then given at 75 mg/m2/3-weekly or 35 mg/m2/weekly. Samples taken for docetaxel PK in first course on day 1 and PK parameters included clearance (CLDoc).

Results

Twenty patients accrued, docetaxel: 3-weekly/weekly = 13:7. EBT parameters (N = 19) (mean, [CV%]): CO2f10 (%/min) 0.051 (106), CO2f20 0.052 (82), kCO2 (min−1) 0.007 (22), AUCCO2,(0–∞) 7.9 (85), AUCCO2,(0–60) 2.64 (81). CLAnt (N = 19) (ml/min); 35.8 (37). Docetaxel PK parameters (N = 19): CLDoc (l/h) = 57.2 (36), tDoc1/2 (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 CLDoc and CLAnt (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.

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Conflict of interest

The listed authors have no conflict of interests. Partial funding by Cancer Trials Australia

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Author notes

  1. S. J. Clarke

    Present address: Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia

Authors and Affiliations

  1. Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, Melbourne, VIC, 8006, Australia

    M. Michael, C. O’Kane & P. Francis

  2. Pharmacology and Developmental Therapeutics Unit, Translational Research Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    C. Cullinane & A. Hatzimihalis

  3. Biostatistics and Clinical Trial, Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    A. Milner

  4. Department of Nuclear Medicine, St Vincent’s Hospital, Fitzroy, Melbourne, VIC, Australia

    R. Booth & S. Schlicht

  5. Department of Medicine and Medical Oncology, Concord Hospital, Sydney, NSW, Australia

    S. J. Clarke

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Michael, M., Cullinane, C., Hatzimihalis, A. et al. Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C14-erythromycin breath test and the antipyrine clearance test. Cancer Chemother Pharmacol 69, 125–135 (2012). https://doi.org/10.1007/s00280-011-1676-y

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