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

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

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44 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)622-633
Aantal pagina's12
TijdschriftBritish Journal of Clinical Pharmacology
Volume64
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - nov. 2007
Extern gepubliceerdJa

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