Hyperhydration with cisplatin does not influence pemetrexed exposure

Nikki de Rouw*, Hieronymus J. Derijks, Luuk B. Hilbrands, René J. Boosman, Berber Piet, Stijn L.W. Koolen, Jacobus A. Burgers, Anne Marie C. Dingemans, Michel M. van den Heuvel, Lizza E.L. Hendriks, Joachim G.J.V. Aerts, Sander Croes, Ron H.J. Mathijssen, Alwin D.R. Huitema, David M. Burger, Bonne Biesma, Rob ter Heine

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Pemetrexed is a cytotoxic drug for first-line treatment of lung cancer. It is often combined with other anticancer drugs such as cisplatin or carboplatin. In clinical practice, hyperhydration regimens are applied to overcome cisplatin-related nephrotoxicity. As pemetrexed is almost completely eliminated from the body by the kidneys, hyperhydration can result in augmented clearance. Furthermore, administration of large quantities of fluid may increase the volume of distribution of pemetrexed. Pharmacokinetics and, thus, efficacy and toxicity may be influenced by hyperhydration. This has not yet been properly studied. We performed a population pharmacokinetic analysis to assess hyperhydration as a covariate for pemetrexed clearance and for volume of distribution A relevant change was defined as >25% increase in clearance or volume of distribution. In our extensive dataset of 133 individuals, we found that hyperhydration did not significantly or relevantly explain variability in pemetrexed clearance (unchanged, P =.196) or volume of distribution (+7% change, P =.002), despite a power of >99% to detect a relevant change. Therefore, dose adjustments of pemetrexed are not required during hyperhydration with cisplatin.

Original languageEnglish
Pages (from-to)871-876
Number of pages6
JournalBritish Journal of Clinical Pharmacology
Volume88
Issue number2
Early online date9 Aug 2021
DOIs
Publication statusPublished - Feb 2022

Bibliographical note

Funding Information:
For NCT03655821 and NCT03656549: This study was supported by ZonMw, the Netherlands (grant number: 848016010). The funding source had no involvement in decisions with regard to study design; data collection, analysis and interpretation; writing of the report and in the decision to submit the article for publication.

Funding Information:
See also COI forms. N.d.R., H.D., R.B., S.C., A.H., D.B., S.K., L.H., M.v.d.H., B.B., R.t.H.: Nothing to disclose. B.P.: Dr Piet reports other from Takeda, other from Bristol Meyer Squibb, other from Astra Zeneca, other from Pfizer, outside the submitted work. J.B.: Dr Burgers reports other from MSD, other from Roche, other from AstraZeneca, outside the submitted work. J.A.: Dr Aerts reports personal fees and nonfinancial support from MSD, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from Amphera, personal fees from Eli Lilly, personal fees from Takeda, personal fees from Bayer, personal fees from Roche, personal fees from Astra Zeneca outside the submitted work. In addition, Dr Aerts has a patent allogenic tumour cell lysate licensed to Amphera, a patent combination immunotherapy in cancer pending, and a patent biomarker for immunotherapy pending. A.D.: Consulting/advisory role for Roche, Eli Lilly, Boegringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda, Pharmamar, Sanofi, outside the submitted work. L.H.: Dr Hendriks reports other from boehringer ingelheim, other from BMS, other from Roche Genentech, grants from Roche Genentech, grants from Boehringer Ingelheim, other from AstraZeneca, personal fees from Quadia, grants from Astra Zeneca, other from Eli Lilly, other from Roche Genentech, other from Pfizer, other from MSD, other from Takeda, nonfinancial support from AstraZeneca, nonfinancial support from Novartis, nonfinancial support from BMS, nonfinancial support from MSD/Merck, nonfinancial support from GSK, nonfinancial support from Takeda, nonfinancial support from Blueprint Medicines, nonfinancial support from Roche Genentech, other from Amgen, nonfinancial support from Janssen Pharmaceuticals, outside the submitted work. A.M.: Dr Mathijssen reports grants from Astellas, grants from Bayer, grants from Boehringer‐Ingelheim, grants from Cristal Therapeutics, grants from Pamgene, grants from Pfizer, grants from Novartis, grants from Roche, grants from Sanofi, grants from Servier, outside the submitted work; In addition, Dr Mathijssen has a patent Pamgene pending.

Funding Information:
For the PERSONAL cohort: This study was supported by ZonMw, the Netherlands (grant number: 152001017). The funding source had no involvement in decisions with regard to study design; data collection, analysis and interpretation; writing of the report and in the decision to submit the article for publication.

Publisher Copyright:
© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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