Hyperhydration with cisplatin does not influence pemetrexed exposure

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.

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration‐induced nephropathy

“…However, the renal damage already caused by methotrexate was not rescued by the administration of folinic acid 26 . A population pharmacokinetic analysis study revealed that hyperhydration during concomitant use of cisplatin did not improve PEM clearance, suggesting that hydration to protect renal function from PEM is not practical 27 . A previous study showed that patients with pre‐existing renal dysfunction experience more adverse effects upon PEM exposure 28 ; thus, it is important to consider evaluating renal function and the risk of renal injury before PEM administration.…”