Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis

Our plain-English summary of Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis, by N. de Rouw, R.J. Boosman, A.D.R. Huitema, et al (Clinical Pharmacokinetics, 2021).

The study

• Authors: N. de Rouw, R.J. Boosman, A.D.R. Huitema, L.B. Hilbrands, E.M. Svensson, H.J. Derijks, M.M. van den Heuvel, D.M. Burger, R. Ter Heine
• Journal: Clinical Pharmacokinetics
• Published: 2021;60(5):649-654
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study examined how the body clears pemetrexed, a chemotherapy drug used for non-small cell lung cancer and mesothelioma, in patients with reduced kidney function. It did not study asbestos exposure. The authors reanalysed blood-level data from the manufacturer's earlier phase I study: 548 measurements from 47 patients whose estimated kidney function (CKD-EPI formula) ranged from 14.4 to 145.6 mL/min. Five of them were below 45 mL/min. Using computer modelling, the authors estimated that clearance by the kidneys accounted for up to 84% (95% confidence interval 69–98%) of total pemetrexed clearance. The manufacturer had previously reported about 50%. In a simulation of 1000 virtual patients, predicted drug exposure in those with creatinine clearance below 45 mL/min was about 1.7 times higher with the new model than with the manufacturer's model. The new model also included a third distribution 'compartment'. In a simulated drug-level curve, this produced higher levels from about 48 hours after a dose, and the authors said it may contribute to prolonged exposure. The authors concluded that kidney function matters more for pemetrexed clearance than previously thought. They noted that few patients had severe kidney impairment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Population pharmacokinetic modelling study (non-linear mixed-effects modelling) of existing phase I data from the manufacturer, plus a computer simulation of 1000 virtual patients comparing the new model with the manufacturer's earlier model
• Who was studied: 47 patients from the manufacturer's renal impairment study, with 548 paired time and concentration observations over 0 to 72 hours after the dose. 36 (77%) were male, median age was 62 years (range 25 to 79), and eGFR (CKD-EPI) ranged from 14.4 to 145.6 mL/min. 42 patients had CKD-EPI of 45 mL/min or more and 5 had less than 45 mL/min. Country and dates are not stated.
• Exposure: The chemotherapy drug pemetrexed, at a median dose of 500 mg/m2 (range 150 to 600). Asbestos exposure was not studied.
• Main results:
  • The data were best described by a three-compartment model. Kidney function estimated with the CKD-EPI formula explained about 45% of the between-patient variability in clearance, reducing it from 38.7% to 21.0%.
  • The typical renal clearance was 3.42 L/h (95% CI 2.80 to 3.99) and the typical non-renal clearance was 0.66 L/h (95% CI 0.24 to 1.13).
  • Renal clearance accounted for up to 84% (95% confidence interval 69 to 98%) of total pemetrexed clearance, compared with the 50% contribution previously reported by the manufacturer.
  • In the simulated patients with creatinine clearance below 45 mL/min, the geometric mean exposure (AUC) was 415 (CV 38.9%) with the new model versus 240 (CV 21.9%) with the manufacturer's model, a ratio of 1.7. In those with 45 mL/min or more, it was 208 (CV 41.4%) versus 172 (CV 29.5%), a ratio of 1.2.
  • In a simulated curve for a typical individual with a clearance of 3 L/h, the third compartment in the new model produced prolonged higher drug levels from about 48 hours after the dose onwards.
• The authors' conclusion: The authors concluded that renal function is more important for pemetrexed clearance than previously thought and should be taken into account in patients with renal impairment. They also concluded that a third compartment may contribute to prolonged exposure during drug washout.
• Limitations the authors state:
  • Few patients had severe renal impairment (eGFR below 30 mL/min), because of toxicity concerns that arose during the phase I study.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Mesothelioma, Work Practice Simulation, EGFR, Epidemiology, confidence interval.

Related studies

• Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis — N. de Rouw, S. Croes, et al. (2019)
• Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage — G. Rombolà, F. Vaira, et al. (2015)
• Pharmacokinetic evaluation of pemetrexed — J.B. Sørensen (2011)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• Anesthetic management and renal function in pediatric patients undergoing cytoreductive surgery with continuous hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin — P. Owusu-Agyemang, R. Arunkumar, et al. (2012)
• Effect of renal function on pemetrexed-induced haematotoxicity — Y. Ando, T. Hayashi, et al. (2016)

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