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.
journal_name
Clin Pharmacokinetjournal_title
Clinical pharmacokineticsauthors
de Rouw N,Boosman RJ,Huitema ADR,Hilbrands LB,Svensson EM,Derijks HJ,van den Heuvel MM,Burger DM,Ter Heine Rdoi
10.1007/s40262-020-00972-1subject
Has Abstractpub_date
2021-01-09 00:00:00eissn
0312-5963issn
1179-1926pii
10.1007/s40262-020-00972-1pub_type
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