Toxicity of pemetrexed during renal impairment explained—Implications for safe treatment
Boosman, René J.; Dorlo, Thomas P.C.; de Rouw, Nikki; Burgers, Jacobus A.; Dingemans, Anne Marie C.; van den Heuvel, Michel M.; Hendriks, Lizza E.L.; Biesma, Bonne; Aerts, Joachim G.J.V.; Croes, Sander; Mathijssen, Ron H.J.; Huitema, Alwin D.R.; ter Heine, Rob
(2021) International Journal of Cancer, volume 149, issue 8, pp. 1576 - 1584
(Article)
Abstract
Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was
... read more
to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m 2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: estimated glomerular filtration rate, neutropenia, non-small cell lung cancer, pemetrexed, prophylactic strategies, Prognosis, Follow-Up Studies, Humans, Middle Aged, Male, Neutropenia/chemically induced, Dose-Response Relationship, Drug, Folic Acid Antagonists/administration & dosage, Tissue Distribution, Lung Neoplasms/drug therapy, Aged, 80 and over, Adult, Female, Kidney Failure, Chronic/chemically induced, Pemetrexed/administration & dosage, Carcinoma, Non-Small-Cell Lung/drug therapy, Aged, Dietary Supplements, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Oncology, Cancer Research, Journal Article
ISSN: 0020-7136
Publisher: Wiley-Liss Inc.
Note: Funding Information: René J. Boosman, Thomas P. C. Dorlo, Nikki de Rouw, Jacobus A. Burgers, Michel M. van den Heuvel, Bonne Biesma, Sander Croes, Alwin D. R. Huitema and Rob ter Heine declare that they have no competing interests. Anne‐Marie C. Dingemans reports financial support from advisory boards Sanofi, Amgen, Bayer, Eli‐Lilly and Roche and as lecturer from Jansen, Pfizer and AstraZeneca. Lizza E. L. Hendriks reports the following conflicts outside the submitted work: research funding from Roche, Boehringer‐Ingelheim, AstraZeneca and Takeda (all to the institution); advisory boards for Boehringer‐Ingelheim, BMS, Eli‐Lilly, Roche, Pfizer, Takeda, MSD and Amgen (all institutional, except once for Roche); travel and conference reimbursements from Roche; funded mentorship sessions with key opinion leaders from AstraZeneca, fees for webinars/medtalks from AstraZeneca and funded interview sessions from Roche (to the institution); local principal investigator in clinical trials from AstraZeneca, Novartis, BMS, MSD, Merck, GSK, Takeda, Blueprint, Roche, Janssen Pharmaceuticals and Miroti. Joachim G. J. V. Aerts reports personal fees and nonfinancial support from MSD, personal fees from BMS, Boehringer‐Ingelheim, Amphera, Eli‐Lilly, Takeda, Bayer, Roche and AstraZeneca, outside the submitted work; in addition, Prof. Aerts has a patent allogenic tumor cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. Ron H. J. Mathijssen reports grants from Astellas, Bayer, Boehringer‐Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Servier and Roche, personal fees from Novartis and Servier and a patent from Pamgene, outside the submitted work. Publisher Copyright: © 2021 UICC. © 2021 UICC.
(Peer reviewed)