Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis
Nikki de Rouw, René J. Boosman, Alwin D. R. Huitema, Luuk B. Hilbrands, Elin M. Svensson, Hieronymus J. Derijks, Michel M. van den Heuvel, David M. Burger, Rob ter Heine
Abstract
BACKGROUND: Pemetrexed is used for the treatment for non-small cell lung cancer and mesothelioma. Patients with renal impairment are withheld treatment with this drug as it is unknown what dose is well tolerated in this population. OBJECTIVE: The purpose of our study was to investigate the pharmacokinetics (PK) of pemetrexed in patients with renal impairment. METHODS: A population PK analysis of pemetrexed was performed using non-linear mixed-effects modelling with phase I data obtained from the manufacturer. Additionally, the impact of renal function on pemetrexed PK was assessed with a simulation study using the developed PK model and a previously developed PK model lacking the phase I data. RESULTS: The dataset included 548 paired observations of 47 patients, with a wide range of estimated glomerular filtration rates (eGFR; 14.4-145.6 mL/min). Pemetrexed PK were best described by a three-compartment model with eGFR (calculated using the Chronic Kidney Disease-Epidemiology Collaboration [CKD-EPI] formula) as a linear covariate on renal pemetrexed clearance. Using the developed model, we found that renal clearance accounts for up to 84% (95% confidence interval 69-98%) of total pemetrexed clearance, whereas the manufacturer previously reported a 50% contribution of renal clearance. CONCLUSION: Renal function is more important for the clearance of pemetrexed than previously thought and this should be taken into account in patients with renal impairment. Furthermore, a third compartment may contribute to prolonged exposure to pemetrexed during drug washout.