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

What is already known about this subject • There are few data about the safety of paclitaxel in patients with clinically significant liver impairment. A study by Venook and colleagues (J Clin Oncol 1998; 16: 1811–19) studied paclitaxel pharmacokinetics (PK) and pharmacodynamics (PD) in patients with liver impairment. The results were mainly descriptive, as detailed PK–PD data were available for only a subgroup of patients. • Another study by Wilson and colleagues found a correlation between tumour involvement of the liver, aspartate aminotransferase and total bilirubin concentrations and reduced paclitaxel clearance in 48 patients with advanced breast cancer in an early combined Phase I/II study (J Clin Oncol 1994; 12: 1621–9). • Finally, the study by Huizing and colleagues (Ann Oncol 1995; 6: 699–704) described two advanced breast cancer patients with liver impairment who experienced higher paclitaxel AUC concentrations and more severe neuropathywhen exposed to paclitaxel 250 mg m −2 as a 3‐h infusion. • Liver impairment has been studied as a covariate within population models of paclitaxel in patients with normal or mildly impaired liver function (Henningsson et al. Eur JCancer 2003; 39: 1105–14; Joerger et al. Clin Cancer Res 2006; 12: 2150–7). Both studies found a negative correlation between total bilirubin concentrations and paclitaxel elimination. What this study adds •  A direct relationship between liver impairment, paclitaxel elimination and susceptibility to neutropenia/thrombopenia. • As a result of PK–PD simulations, suggestions could be made for (further) dose adaptations for patients with more severe liver impairment. 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 ( R 2  = −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.