Pharmacokinetic evaluation of pemetrexed

Our plain-English summary of Pharmacokinetic evaluation of pemetrexed, by J.B. Sørensen (Expert Opinion on Drug Metabolism & Toxicology, 2011).

The study

• Author: J.B. Sørensen
• Journal: Expert Opinion on Drug Metabolism & Toxicology
• Published: 2011;7(7):919-28
• Type of article: Review
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Pemetrexed is a multi-targeted antifolate cytotoxic agent that has demonstrated activity in a number of very common cancer types including NSCLC in both first- and second-line settings and in the treatment of malignant mesothelioma.

Areas Covered: This article focuses on all of the currently published pharmacokinetic data of pemetrexed reviewing a number of different scenarios and patient populations. All the articles reviewed in this manuscript are from peer-reviewed English-spoken literature without any limitations to the time of publication.

Expert Opinion: Pemetrexed's clearance correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic or targeted agents. It is the author's opinion that pemetrexed is already a valuable cytotoxic agent which has proved useful in several malignancies. However, future trials might expand on the combined use of pemetrexed with other targeted agents that could be beneficial to other selected patients harboring relevant mutations or other biological features.

In plain English

This single-author review covered pharmacokinetic studies of pemetrexed, a chemotherapy drug for non-small cell lung cancer and malignant mesothelioma. It included peer-reviewed English-language articles and did not study asbestos. The drug was removed mainly by the kidneys; in one study, clearance correlated with GFR (r2 = 0.736). In 31 patients with pleural effusions or ascites, drug levels stayed within the range seen without such fluid. A rat study found lower peak blood levels with dosing into the pleural space than into a vein. A monkey study found less than 2% penetration into spinal fluid. In patients with creatinine clearance of at least 60 ml/min, moderate-dose aspirin did not alter pharmacokinetics; the author warned this may not apply to high-dose aspirin or lower clearance. Ibuprofen was associated with a 16% reduction in clearance, and those data cannot be extrapolated below creatinine clearance of 80 ml/min. The author concluded that pemetrexed has a safe, predictable toxicity profile, especially with folic acid and vitamin B12, and that its use is limited to creatinine clearance of at least 45 ml/min.

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: Review (drug evaluation) of published pharmacokinetic studies of pemetrexed
• Who was studied: Published peer-reviewed English-language studies of pemetrexed pharmacokinetics, with no time limit. These included studies of cancer patients in Phase I and II trials, rats and rhesus monkeys.
• Exposure: The chemotherapy drug pemetrexed, alone or combined with other drugs. Asbestos exposure was not studied.
• Main results:
  • In a reviewed population analysis of 287 patients from 10 Phase II trials (Latz et al.), typical total clearance of pemetrexed was 91.6 ml/min.
  • In the reviewed studies, pemetrexed was eliminated mainly by the kidneys as unchanged drug.
  • In a reviewed Phase I study of patients with normal or impaired kidney function (Mita et al., 47 patients), pemetrexed plasma clearance correlated with GFR (r2 = 0.736; p less than 0.0001).
  • In a reviewed study of 31 patients with third-space fluid (pleural effusions or ascites), pemetrexed plasma concentrations were within the range seen in patients without such fluid.
  • In a reviewed rat study, peak plasma concentration was lower after intrapleural than after intravenous administration of 10 mg/kg (14.36 vs 29.83 µg/ml; p = 0.008). AUC and clearance did not differ significantly by route.
  • In a reviewed rhesus monkey study, penetration of pemetrexed into cerebrospinal fluid was less than 2%.
  • In a reviewed drug interaction study, patients had creatinine clearance of at least 60 ml/min and took aspirin 325 mg every 6 hours. In these patients, aspirin did not alter pemetrexed pharmacokinetics.
  • In the reviewed ibuprofen interaction study (27 patients), ibuprofen was associated with a 16% reduction in pemetrexed clearance. It was also associated with a 15% increase in maximum plasma concentration and a 20% increase in AUC.
  • In a reviewed study combining pemetrexed with cyclophosphamide, pemetrexed clearance and central volume of distribution were each around 40% lower than with pemetrexed alone.
• The authors' conclusion: The author concluded that pemetrexed has a safe and predictable toxicity profile, especially when folic acid and vitamin B12 are given. The author also concluded that its clearance correlates with kidney function.
• Limitations the authors state:
  • The author stated that experience in patients with more pronounced kidney impairment is limited, so use is limited to patients with creatinine clearance of at least 45 ml/min.
  • The author stated that pemetrexed has not been evaluated in patients with more pronounced liver impairment.
  • The author stated that the aspirin finding may not apply to high-dose aspirin or to patients with creatinine clearance below 60 ml/min.
  • The author stated that the ibuprofen data cannot be extrapolated to patients with creatinine clearance below 80 ml/min.

Topics

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

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Antifolate, Second-Line Therapy, Malignant Mesothelioma.

Related studies

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• The role of pemetrexed combined with targeted agents for non-small cell lung cancer — K. Konopa, J. Jassem (2010)
• Pemetrexed disodium: a novel antifolate clinically active against multiple solid tumors — A.R. Hanauske, V. Chen, et al. (2001)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)
• 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)

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