Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Joerger, M. et al.

M. Joerger, A. D. R. Huitema, M.T. Huizing, P. H. B. Willemse, A. de Graeff, H. Rosing, J. H. M. Schellens, J.H. Beijnen, J.B. Vermorken,

Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study.

AIMS: To assess quantitatively the safety and pharmacology of paclitaxel in patients with moderate to severe hepatic impairment. METHODS: Solid tumour patients were enrolled into five liver function cohorts as defined by liver transaminase and total bilirubin concentrations. Paclitaxel was administered as a 3-h intravenous infusion at doses ranging from 110 to 175 mg m(-2), depending on liver impairment. Covariate and semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) population modelling was used to describe the impact of liver impairment on the pharmacology and safety of paclitaxel. RESULTS: Thirty-five patients were included in the study, and PK data were assessed for 59 treatment courses. Most patients had advanced breast cancer (n = 22). Objective responses to paclitaxel were seen in four patients (11%). Patients in higher categories of liver impairment had a significantly lower paclitaxel elimination capacity (R2 = -0.38, P = 0.05), and total bilirubin was a significant covariate to predict decreased elimination capacity with population modelling (P = 0.002). Total bilirubin was also a significant predictor of increased haematological toxicity within the integrated population PK-PD model (P < 10(-4)). Data simulations were used to calculate safe initial paclitaxel doses, which were lower than the administered doses for liver impairment cohorts III-V. CONCLUSIONS: Total bilirubin is a good predictor of paclitaxel elimination capacity and of individual susceptibility to paclitaxel-related myelosuppression in cancer patients with moderate to severe liver impairment. The proposed, adapted paclitaxel doses need validation in prospective trials.[1]

References

Safety and pharmacology of paclitaxel in patients with impaired liver function: a population pharmacokinetic-pharmacodynamic study. Joerger, M., Huitema, A.D., Huizing, M.T., Willemse, P.H., de Graeff, A., Rosing, H., Schellens, J.H., Beijnen, J.H., Vermorken, J.B. Br. J. Clin. Pharmacol (2007) [Pubmed]

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