Population analysis of a 24-h paclitaxel infusion in advanced endometrial cancer: a gynaecological oncology group study

Abstract

Aims: To examine determinants of paclitaxel disposition and the association between paclitaxel exposure and toxicity or survival in patients with advanced stage or recurrent endometrial cancer treated with doxorubicin plus paclitaxel.

Methods: A limited sampling scheme was used to examine the population pharmacokinetics of paclitaxel in 160 patients from one arm of a randomized Phase III trial of doxorubicin plus paclitaxel or cisplatin. Four plasma samples per patient were collected at approximately 0, 3, 22 and 27 h after the first 24-h infusion of paclitaxel and submitted to the Gynecological Oncology Group (GOG) Pharmacology Core Laboratory. Total paclitaxel concentrations were quantified by LC/MS and paclitaxel disposition was examined using NONMEM. Paclitaxel exposure was evaluated for associations with toxicity or survival.

Results: Patient weight, age and serum glutamic-oxaloacetic transaminase level were determinants of paclitaxel clearance (clearance increased 0.437 l h-1 kg-1; decreased 0.223 l h-1 year-1 and 0.105 l h-1 IU-1). Bayesian shrinkage was minimal for this parameter. In different measures of paclitaxel exposure, AUC was most predictive of toxicity, with higher AUC associated with granulocytopenia [probability of 1% at AUC=1 to 22% at AUC=4 microg l-1 h-1 for performance status (PS)=0]. PS was more strongly associated with survival than disease stage and higher paclitaxel AUC was associated with worse survival irrespective of PS and stage.

Conclusions: Paclitaxel AUC is an independent predictor of granulocytopenia and survival in patients with advanced stage or recurrent endometrial cancer. Future studies are needed to validate the latter finding. This study confirms the appropriateness of evaluating pharmacokinetics and pharmacodynamics in multicentre oncology trials.

Figure 1

Frequency histogram for sample collection vs. relative time after the start of infusion

Figure 2

Diagnostic plots for pharmacokinetic models. (A) Observed vs. typical predicted total paclitaxel concentrations. Data (•), Line of Unity (). (B) Ninety-five percent prediction interval () with the mean predicted serum concentration (). The observed paclitaxel concentrations (○) are overlaid on the interval

Figure 3

Estimated probability curves with 95% confidence intervals. (A) Probability curves for Gynecological Oncology Group (GOG) performance status 0. (B) Probability curves for performance status 2. Solid lines, Probability curves; horizontal lines, 95% confidence intervals for the probability curves

Figure 4

Effect of low vs. high paclitaxel AUC on survival (proportion surviving provided in months from enrolment) in patients with any performance status (A); with good performance status (PS = 0, B); or with poor performance status (PS = 1 or 2, C). Low AUC: <2.33 µg h⁻¹ l⁻¹ (bin 1); high AUC: ≥;2.33 µg h⁻¹ l⁻¹ (bins 2–5)