Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis

Our plain-English summary of Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis, by N. de Rouw, S. Croes, R. Posthuma, et al (Lung Cancer, 2019).

The study

• Authors: N. de Rouw, S. Croes, R. Posthuma, D.E. Agterhuis, J.J.A.O. Schoenmaekers, H.J. Derijks, D.M. Burger, A.M. Dingemans, R. Ter Heine
• Journal: Lung Cancer
• Published: 2019;130:156-158
• Type of article: Case report
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Pemetrexed is indicated for non-small cell lung cancer and mesothelioma. Dosing is based on body surface are (BSA), while renal function is the only determinant for exposure and thus toxicity. BSA-based dosing introduces large variability in exposure and may lead to (hemato)toxicity in patients with impaired renal function. Therefore, pemetrexed is contraindicated in renal impairment. The presented cases provide proof-of-concept for pharmacokinetically-guided dosing of pemetrexed in a haemodialysis patient and a patient with mild renal impairment.

Methods: The pharmacokinetic target was an area under the concentration-time curve (AUC) of 123-205 mg·h/L. Using a previously developed population pharmacokinetic model, individual pharmacokinetics were estimated.

Results: Both patients had an exposure above target after the initial dose, but a proportional dose reduction resulted in a therapeutic exposure in both patients (185 and 166 mg·h/L, respectively), that was well-tolerated. Interestingly, a threefold increase in systemic clearance of pemetrexed was observed during hemodialysis (from 1.00 L/h to 3.01 L/h), which approximates the population clearance of pemetrexed.

Conclusion: Altogether, we showed that pharmacokinetically-guided dosing of pemetrexed may be a feasible strategy for patients with lung cancer and renal impairment.

Copyright © 2019. Published by Elsevier B.V.

In plain English

This is a report of two cases of non-small cell lung cancer (NSCLC), not mesothelioma. Asbestos exposure was not studied. Pemetrexed, a drug used for NSCLC and mesothelioma, is normally withheld when kidney function is poor. The authors measured blood levels of the drug and adjusted doses to reach a target exposure (AUC) of 123 to 205 mg·h/L. The first patient, a 75-year-old man on hemodialysis, had an AUC of 230 mg·h/L after a 250 mg dose. At 200 mg, it was 185 mg·h/L. His pemetrexed clearance was 1.00 L/h off dialysis and 3.01 L/h during dialysis. The second patient, a 78-year-old woman with a creatinine clearance of 41 mL/min, had an AUC of 260 mg·h/L after 755 mg. At 500 mg, it was 166 mg·h/L. The authors described treatment as well tolerated in both. The first patient later developed neuropathy in both hands. The second reported vertigo, shortness of breath and some hearing loss. The authors concluded that this dosing approach may be a feasible strategy in renal 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: Case report of two patients (therapeutic drug monitoring used to guide pemetrexed dosing)
• Who was studied: Two patients with non-small cell lung cancer and impaired kidney function: a 75-year-old man with stage 4A NSCLC and end-stage renal disease on hemodialysis, and a 78-year-old woman with stage 3A NSCLC and an estimated creatinine clearance of 41 mL/min. No mesothelioma patients were included.
• Exposure: The chemotherapy drug pemetrexed, given with carboplatin, with doses adjusted according to measured drug exposure. No asbestos or fiber exposure was studied.
• Main results:
  • Hemodialysis patient: the AUC after the first 250 mg dose was estimated at 230 mg·h/L, above the target, so the dose was lowered to 200 mg.
  • Hemodialysis patient: at 200 mg, the estimated AUC was 185 mg·h/L, within the target range.
  • Hemodialysis patient: pemetrexed clearance was estimated at 1.00 L/h without hemodialysis and 3.01 L/h during hemodialysis.
  • Hemodialysis patient: therapy was described as well tolerated at the three-cycle evaluation, and a partial response was seen after the fourth cycle. The patient developed neuropathy in both hands, and no maintenance pemetrexed was started.
  • Second patient (creatinine clearance 41 mL/min): the estimated AUC was 260 mg·h/L after the initial 755 mg dose, which was then reduced to 500 mg.
  • Second patient: at 500 mg, the estimated AUC was 166 mg·h/L, within the target range.
  • Second patient: after three cycles, the patient reported vertigo, shortness of breath and some hearing loss. A hearing test did not confirm worse hearing. After the fourth cycle there were no signs of tumor recurrence, and a temporary decrease in haemoglobin and platelets was observed.
• The authors' conclusion: The authors concluded that pharmacokinetically-guided dosing of pemetrexed may be a feasible way to allow safe treatment in renal impairment, where the drug is usually contraindicated. They called for evaluation in a prospective clinical 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, Lung Cancer.

Related studies

• Rethinking the Application of Pemetrexed for Patients with Renal Impairment: A Pharmacokinetic Analysis — N. de Rouw, R.J. Boosman, et al. (2021)
• 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)
• Pemetrexed induces apoptosis in malignant mesothelioma and lung cancer cells through activation of reactive oxygen species and inhibition of sirtuin 1 — K.E. Hwang, Y.S. Kim, et al. (2015)
• Pemetrexed-induced scleroderma-like conditions in the lower legs of a patient with non-small cell lung carcinoma — K. Ishikawa, T. Sakai, et al. (2016)
• Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis — Z. Schlei, W. Tan, et al. (2018)
• Dexamethasone alleviates pemetrexed-induced senescence in Non-Small-Cell Lung Cancer — H. Ge, J. Ke, et al. (2018)

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