RT Journal Article
SR Electronic
T1 Time-to-Event Analysis of Paclitaxel-Associated Peripheral Neuropathy in Advanced Non–Small-Cell Lung Cancer Highlighting Key Influential Treatment/Patient Factors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 430
OP 438
DO 10.1124/jpet.120.000053
VO 375
IS 3
A1 Ojara, Francis W.
A1 Henrich, Andrea
A1 Frances, Nicolas
A1 Huisinga, Wilhelm
A1 Hartung, Niklas
A1 Joerger, Markus
A1 Kloft, Charlotte
YR 2020
UL http://jpet.aspetjournals.org/content/375/3/430.abstract
AB Paclitaxel-associated peripheral neuropathy (PN), a major dose-limiting toxicity, significantly impacts patients’ quality of life/treatment outcome. Evaluation of risk factors often ignores time of PN onset, precluding the impact of time-dependent factors, e.g., drug exposure, needed to comprehensively characterize PN. We employed parametric time-to-event (TTE) analysis to describe the time course of risk of first occurrence of clinically relevant PN grades ≥2 (PN2+, n = 105, common terminology criteria v4.0) and associated patient/treatment characteristics, leveraging data from 365 patients (1454 cycles) receiving paclitaxel every 3 weeks (plus carboplatin AUC = 6 or cisplatin 80 mg/m2) for ≤6 cycles. Paclitaxel was intravenously administered (3 hours) as standard 200-mg/m2 doses (n = 182) or as pharmacokinetic-guided dosing (n = 183). A cycle-varying hazard TTE model linking surge in hazard of PN2+ to paclitaxel administration [PN2+ proportions (i.e., cases per 1000 patients), 1st day, cycle 1: 4.87 of 1000; cycle 6: 7.36 of 1000] and linear decline across cycle (last day, cycle 1: 1.64 of 1000; cycle 6: 2.48 of 1000) adequately characterized the time-varying hazard of PN2+. From joint covariate evaluation, PN2+ proportions (1st day, cycle 1) increased by 1.00 per 1000 with 5-μmol·h/l higher paclitaxel exposure per cycle (AUC between the start and end of a cycle, most relevant covariate), 0.429 per 1000 with 5-year higher age, 1.31 per 1000 (smokers vs. nonsmokers), and decreased by 0.670 per 1000 (females vs. males). Compared to 200 mg/m2 dosing every 3 weeks, model-predicted cumulative risk of PN2+ was significantly higher (42%) with 80 mg/m2 weekly dosing but reduced by 11% with 175 mg/m2 dosing every 3 weeks. The established TTE modeling framework enables quantification and comparison of patient’s cumulative risks of PN2+ for different clinically relevant paclitaxel dosing schedules, sparing patients PN2+ to improve paclitaxel therapy.SIGNIFICANCE STATEMENT Characterization of risk factors of paclitaxel-associated peripheral neuropathy (PN) typically involves time-independent comparison of PN odds in patient subpopulations, concealing the impact of time-dependent factors, e.g., changing paclitaxel exposure, required to comprehensively characterize PN. We developed a parametric time-to-event model describing the time course in risk of clinically relevant paclitaxel-associated PN, identifying the highest risk in older male smokers with higher paclitaxel area under the plasma concentration-time curve between the start and end of a cycle. The developed framework enabled quantification of patient’s risk of PN for clinically relevant paclitaxel dosing schedules, facilitating future dosing decisions.