Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Autor: Boosman RJ; Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Amsterdam, The Netherlands., Dorlo TPC; Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Amsterdam, The Netherlands., de Rouw N; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Pharmacy, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands., Burgers JA; Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Dingemans AC; Department of Pulmonary Diseases, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.; Department of Pulmonology, Erasmus MC, Rotterdam, The Netherlands., van den Heuvel MM; Department of Pulmonology, Radboud university medical center, Nijmegen, The Netherlands., Hendriks LEL; Department of Pulmonary Diseases, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands., Biesma B; Department of Pulmonary Diseases, Jeroen Bosch Hospital, 's Hertogenbosch, The Netherlands., Aerts JGJV; Department of Pulmonology, Erasmus MC, Rotterdam, The Netherlands., Croes S; Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands., Huitema ADR; Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek-The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Department of Clinical Pharmacy, Utrecht University Medical Center, Utrecht University, Utrecht, The Netherlands.; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Ter Heine R; Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2021 Oct 15; Vol. 149 (8), pp. 1576-1584. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.1002/ijc.33721
Abstrakt: 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 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.
(© 2021 UICC.)
Databáze: MEDLINE
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