Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment

Pemetrexed is a cornerstone in chemo(immunotherapy) of non-small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra-patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min). The pemetrexed dose was calculated based on renal function to reach a target AUC, and patients received oral folinic acid prophylaxis 45 mg four times daily on Days 2-15 of each cycle. Endpoints included safety (incidence of hematological and non-hematological toxicity, treatment delays) and pharmacokinetics in line with regulatory guidance for renal impairment trials. Six patients with an estimated glomerular filtration rate (eGFR) between 26 and 41 mL/min were included. All patients were successfully escalated to the full dose. Adverse event patterns and pharmacokinetics were comparable to those in patients with normal renal function. Grade I/II anemia occurred in five patients (already present at baseline). One occurrence of grade IV neutropenia was observed, which resolved without intervention. Moreover, in three patients, a 1-week treatment delay occurred. Treatment resulted in a response in four patients (n = 1 complete response, n = 2 partial response, n = 1 stable disease). Pemetrexed can be safely administered in patients with impaired renal function when the dose is calculated based on renal function and folinic acid prophylaxis is administered, thereby enabling an effective treatment modality for patients that, thus far, could not be treated.

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Publication Details

Journal
Clinical Pharmacology & Therapeutics
Published
2025-05-27
DOI
https://doi.org/10.1002/cpt.3735
Primary Topic
Occupational and environmental lung diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment

C. Steendam, Lizza Hendriks, Bianca van Veggel, Mart P. Kicken et al.
Clinical Pharmacology & Therapeutics
Occupational and environmental lung diseases
article

Folinic Acid Prophylaxis and Dose Adjustments Enable Safe Treatment with Pemetrexed in Patients with Renal Impairment

C. Steendam, Lizza Hendriks, Bianca van Veggel, Mart P. Kicken, Alwin D. R. Huitema, Rob ter Heine, Anne‐Marie C. Dingemans, Nikki de Rouw, Daphne W. Dumoulin, Bonne Biesma, Leila S. Otten, Sjaak A. Burgers, Michel M. van den Heuvel, Sander Croes, Berber Piet, Ron H.J. Mathijssen, Maarten J. Deenen, Hieronymus J. Derijks, Ben van den Borne
article en

Abstract

Pemetrexed is a cornerstone in chemo(immunotherapy) of non-small cell lung cancer and mesothelioma; however, it is contraindicated in patients with renal impairment due to severe toxicity concerns. Therefore, a large proportion of patients is withheld from effective chemo(immunotherapy). We performed an intra-patient 3 + 3 dose escalation renal impairment study (eGFR < 45 mL/min). The pemetrexed dose was calculated based on renal function to reach a target AUC, and patients received oral folinic acid prophylaxis 45 mg four times daily on Days 2-15 of each cycle. Endpoints included safety (incidence of hematological and non-hematological toxicity, treatment delays) and pharmacokinetics in line with regulatory guidance for renal impairment trials. Six patients with an estimated glomerular filtration rate (eGFR) between 26 and 41 mL/min were included. All patients were successfully escalated to the full dose. Adverse event patterns and pharmacokinetics were comparable to those in patients with normal renal function. Grade I/II anemia occurred in five patients (already present at baseline). One occurrence of grade IV neutropenia was observed, which resolved without intervention. Moreover, in three patients, a 1-week treatment delay occurred. Treatment resulted in a response in four patients (n = 1 complete response, n = 2 partial response, n = 1 stable disease). Pemetrexed can be safely administered in patients with impaired renal function when the dose is calculated based on renal function and folinic acid prophylaxis is administered, thereby enabling an effective treatment modality for patients that, thus far, could not be treated.

Clinical Pharmacology & TherapeuticsVol. 118(3)
Radboud University Nijmegen (NL), Utrecht University (NL), Leiden University Medical Center (NL), Maastricht University Medical Centre (NL), Catharina Ziekenhuis (NL), Radboud University Medical Center (NL), The Netherlands Cancer Institute (NL), University Medical Center Utrecht (NL), Maastricht University (NL), Amphia Ziekenhuis (NL), Radboud Institute for Molecular Life Sciences (NL), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NL), Princess Máxima Center (NL), Erasmus MC Cancer Institute (NL), Jeroen Bosch Ziekenhuis (NL)
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Good health and well-being
Openalex Percentile: Top 81%
Occupational and environmental lung diseases
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