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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Time-to-Event Analysis of Paclitaxel-Associated Peripheral Neuropathy in Advanced Non–Small-Cell Lung Cancer Highlighting Key Influential Treatment/Patient Factors

Francis W. Ojara, Andrea Henrich, Nicolas Frances, Wilhelm Huisinga, Niklas Hartung, Markus Joerger and Charlotte Kloft
Journal of Pharmacology and Experimental Therapeutics December 2020, 375 (3) 430-438; DOI: https://doi.org/10.1124/jpet.120.000053
Francis W. Ojara
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Andrea Henrich
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Nicolas Frances
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Wilhelm Huisinga
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Niklas Hartung
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Markus Joerger
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Charlotte Kloft
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany (F.W.O., A.H., C.K.); Graduate Research Training Program PharMetrX, Germany (F.W.O., A.H.); Department of Translational Modeling and Simulation, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (N.F.), Institute of Mathematics, University of Potsdam, Potsdam, Germany (N.H, W.H.); and Department of Oncology and Hematology, Cantonal Hospital, St. Gallen, Switzerland (M.J.)
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Abstract

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.

Footnotes

    • Received April 14, 2020.
    • Accepted September 3, 2020.
  • There was no outside funding for this paper. C.K. and W.H. report grants from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grünenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA, AstraZenaca UK Limited and Sanofi) for the PharMetrX program. C.K. reports grants for the Innovative Medicines Initiative-Joint Undertaking [Drug Disease Modelling Resources (DDMoRe)], Diurnal Ltd., the Federal Ministry of Education and Research within the Joint Programming Initiative on Antimicrobial Resistance Initiative (JPIAMR) and from the European Commission within the Horizon 2020 framework programme (“FAIR”), all outside the submitted work.

  • https://doi.org/10.1124/jpet.120.000053.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 375 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 3
1 Dec 2020
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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Time-to-Event Analysis of Paclitaxel Peripheral Neuropathy

Francis W. Ojara, Andrea Henrich, Nicolas Frances, Wilhelm Huisinga, Niklas Hartung, Markus Joerger and Charlotte Kloft
Journal of Pharmacology and Experimental Therapeutics December 1, 2020, 375 (3) 430-438; DOI: https://doi.org/10.1124/jpet.120.000053

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Research ArticleChemotherapy, Antibiotics, and Gene Therapy

Time-to-Event Analysis of Paclitaxel Peripheral Neuropathy

Francis W. Ojara, Andrea Henrich, Nicolas Frances, Wilhelm Huisinga, Niklas Hartung, Markus Joerger and Charlotte Kloft
Journal of Pharmacology and Experimental Therapeutics December 1, 2020, 375 (3) 430-438; DOI: https://doi.org/10.1124/jpet.120.000053
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