High and individually variable enzymatic activity precludes accurate determination of pemetrexed, methotrexate and their polyglutamate metabolite concentrations in plasma

Stoop, Marcel P.; Visser, Sabine; Dijk, Evert van; Aerts, Joachim; Stricker, Bruno H.; Luider, Theo M.

doi:10.1016/j.jpba.2017.09.014

Cited by 5 publications

(5 citation statements)

References 17 publications

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“…Thus, the expression level of FPGS and the amount of PEM polyglutamates in renal tubular cells may affect PEM‐induced nephrotoxicity. However, it is difficult to obtain renal tubular cells in routine clinical practice, and the quantitative evaluation of plasma PEM polyglutamates has been difficult because of the highly different protease activities of individuals 20 . Therefore, detecting FPGS SNPs may help predict the risk of PEM‐related renal damage.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is difficult to obtain renal tubular cells in routine clinical practice, and the quantitative evaluation of plasma PEM polyglutamates has been difficult because of the highly different protease activities of individuals. 20 Therefore, detecting FPGS SNPs may help predict the risk of PEM-related renal damage. Searching for SNPs related to adverse events during PEM administration may be valuable for the long-term continuation of PEM.…”

Section: Discussionmentioning

confidence: 99%

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Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration‐induced nephropathy

Mitarai

Tanino

Nakashima

et al. 2023

Brit J Clinical Pharma

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AimsLong‐term administration of pemetrexed (PEM) in patients with lung cancer can cause renal damage, leading to treatment discontinuation. Previous reports have suggested that specific single nucleotide polymorphisms (SNPs) in the folylpolyglutamate synthase (FPGS) gene affect therapeutic efficacy; however, whether the FPGS SNPs affect renal function is unclear. Identifying SNPs related to renal damage during PEM administration may help predict the decrease in renal function caused by PEM.MethodsWe retrospectively examined age, sex, body weight, total administered PEM, combined platinum, estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) levels before and after PEM administration in patients with non‐small cell lung cancer and searched for the alleles of FPGS SNPs (rs1544105 and rs10106) using DNA extracted from whole blood samples of patients.ResultsRenal function decreased after PEM administration in 26 cases overall. The SCr and eGFR indices showed decreased renal function irrespective of concomitant cisplatin use. Based on promoter activity and miRNA binding predictions, rs1544105‐C and rs10106‐T were hypothesized to increase FPGS expression. Single SNP analyses showed no significant differences in renal function between groups with and without each SNP. Multiple regression analysis revealed that the most significant factors for decreased renal function were sex on SCr and the number of SNPs on eGFR. In subgroup analyses, the patients with rs10106‐T showed a decline in renal function in the older group.ConclusionsThe number of FPGS SNPs may contribute to PEM‐induced renal impairment. Detecting FPGS SNPs may help predict PEM‐induced renal damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration‐induced nephropathy

Mitarai

Tanino

Nakashima

et al. 2023

Brit J Clinical Pharma

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“…Measurement of the intracellular polyglutamated forms of pemetrexed thus would be an ideal marker for its pharmacological effects. However, the development of an analytic method has proven to be challenging [106]. Although it is unclear how well the polyglutamylated forms of pemetrexed correlate to pemetrexed plasma concentrations, a plasma exposure-toxicity relationship has been well-established in a generally broad range of doses (126-1362 mg) [107][108][109].…”

Section: Pemetrexedmentioning

confidence: 99%

Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer

Boosman

Burgers

Smit

et al. 2021

Drugs

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In oncology, and especially in the treatment of non-small-cell lung cancer (NSCLC), dose optimization is often a neglected part of precision medicine. Many drugs are still being administered in "one dose fits all" regimens or based on parameters that are often only minor determinants for systemic exposure. These dosing approaches often introduce additional pharmacokinetic variability and do not add to treatment outcomes. Fortunately, pharmacological knowledge is increasing, providing valuable information regarding the potential of, for example, therapeutic drug monitoring. This article focuses on the evidence for the most promising and easily implemented optimized dosing approaches for the small-molecule inhibitors, chemotherapeutic agents, and monoclonal antibodies as treatment options currently approved for NSCLC. Despite limitations such as investigations having been conducted in oncological diseases other than NSCLC or the retrospective origin of many analyses, an alternative dosing regimen could be beneficial for treatment outcomes, prescriber convenience, or financial burden on healthcare systems. This review of the literature provides recommendations on the implementation of dose optimization and advice regarding promising strategies that deserve further research in NSCLC.

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“…For this analysis, blood samples were centrifuged and packed red blood cells (RBC) were stored at −20°C until analysis (Limelette et al, 2003;Stoop et al, 2018).…”

Section: Experimental Design and Sample Collection For The Lt-studymentioning

confidence: 99%

Pharmacokinetics of low‐dose methotrexate in horses

Rostang

Desjardins

Espana

et al. 2020

Vet Pharm & Therapeutics

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This study aimed to investigate both the pharmacokinetic behavior and tolerance of methotrexate (MTX) in horses to design a specific dosing regimen as a new immunomodulatory drug for long‐term treatment. To determine the primary plasma pharmacokinetic variables after single intravenous, subcutaneous or oral administration, six horses were administered 0.3 mg/kg MTX in a crossover design study. After a 10‐week washout, MTX was administered subcutaneously to three of the six previously treated horses at a dose of 0.3 mg/kg once per week for 3 months. In both studies, MTX and metabolite concentrations were measured using LC‐MS/MS. The absolute bioavailability of MTX was 73% following subcutaneous administration but less than 1% following oral administration. The plasma clearance was 1.54 ml min−1 kg−1 (extraction ratio = 2%). After 24 hr, plasma concentrations were below the LOQ. No adverse effects were noted except for a moderate reversible elevation in liver enzymes (GLDH). With regards to the main metabolites of MTX, very low concentrations of 7‐hydroxy‐MTX were found, whereas polyglutamated forms (mainly short chains) were found in red blood cells. A subcutaneous dose of 0.2 mg kg−1 week−1 may be safe and relevant in horses, although this has yet to be clinically confirmed.

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High and individually variable enzymatic activity precludes accurate determination of pemetrexed, methotrexate and their polyglutamate metabolite concentrations in plasma

Cited by 5 publications

References 17 publications

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration‐induced nephropathy

Effects of single nucleotide polymorphisms of the folylpolyglutamate synthase gene on pemetrexed administration‐induced nephropathy

Optimized Dosing: The Next Step in Precision Medicine in Non-Small-Cell Lung Cancer

Pharmacokinetics of low‐dose methotrexate in horses

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