Examining the relationship between paclitaxel exposure and peripheral neuropathy in non-small cell lung cancer
Francis W. Ojara (1,2), Andrea Henrich (1,2), Niklas Hartung (1,6), Markus Joerger (3), M. Roessler (5), J. Von Pawel (4), Wilhelm Huisinga (6), Charlotte Kloft (1)
(1) Dept. Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) Graduate Research Training program PharMetrX, Germany, (3) Dept. of Oncology & Haematology, Cantonal Hospital, St Gallen, Switzerland, (4) Pneumology clinic, Asklepos Fachkliniken, Gautig, Germany, (5) CESAR central office, Vienna, Austria and (6) Institute of Mathematics, Universitaet Potsdam, Germany
Objectives: Peripheral neuropathy (PN) is a dose-limiting, cumulative adverse event of paclitaxel (PTX) reported by more than 20% of patients on PTX therapy. High PTX doses and exposure (time above a threshold plasma concentration of 0.05 μM, TC>0.05µM) are associated with increased risk of PN from standard statistical tests [1,2]. In the CEPAC-TDM study [3], PK-guided dosing of PTX significantly lowered clinically important PN (i.e. grades 2 or 3). This work examined the impact of consistent PTX dose levels and exposure, at an individual level, on PN in advanced non-small-cell lung cancer patients with the goal of dose adaptation to reduce the burden of PN.
Methods: Patients (n = 249) who received consistent PTX doses (not varying more than 50 mg across cycles) every 3 weeks until the first incidence of clinically important PN or across all treatment cycles were considered from a dose adaptation study: CEPAC-TDM [3]. Cisplatin or carboplatin were concomitantly administered. PN was classified using the common terminology criteria, version 4.0 [4]. Exposure (dose, TC>0.05µM and AUC∞) at the cycle of incidence and exposure in the first treatment cycle were considered as predictors of clinically important PN and clinically non-important PN (i.e. grades 0 or 1), respectively. The risk of clinically important PN with PTX exposure at the cycle of incidence was examined using binary logistic regression (LR) models considering a linear drug effect. The dataset was formatted in R and modelling was performed using NONMEM 7.4.
Results: 88 of the 249 patients reported clinically important PN. Absolute dose was identified as a statistically significant predictor of PN using the likelihood ratio test at α=0.05 (1 degree of freedom). The odds of clinically important PN increased 5% for every 10 mg increase in absolute dose, OR (95% CI): 1.05 (1.002-1.106). Relative dose (based on body surface area), TC>0.05µM and AUC∞ were not statistically significant predictors of clinically important PN.
Conclusions: Using the LR model we successfully quantified the relationship between PTX dose and clinically important PN. In the subsequent steps, we will employ Markov chain models to examine transition rates between different PN grades and undertake time-to-event analysis to additionally account for censored observations, with the goal of determining the impact of PTX exposure on transitions between different PN grades.
References:
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