New laboratory method has a higher limit of detection and. Methotrexate is a useful antimetabolite for the treatment of both benign and malignant pro. Its high effectivenessprice ratio also won extensive application in ophthalmology. Jan 17, 2020 the clinical pharmacology of methotrexate has not been well studied in older individuals.
The pharmacology and clinical use of methotrexate nejm. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. The apparent methotrexate clearance 11 versus lhour, the auc 2. When the pharmacokinetics and potential toxicity of this drug are. We describe two fatal cases of low dose methotrexate mtx toxicity in patients with psoriasis, emphasizing the factors that exacerbate mtx toxicity. The first patient was a 50yearold male of psoriasis on intermittent treatment with mtx. Methotrexate, the most widely used antimetabolite in cancer chemotherapy, has an essential role in the treatment of such diverse diseases as acute lymphocytic leukemia, nonhodgkins lymphoma, osteosarcoma, choriocarcinoma, head and neck cancer, and breast cancer. Methotrexate overdose in clinical practice bentham science.
Mar 19, 2002 despite the recent introduction of biological response modifiers and potent new smallmolecule antirheumatic drugs, the efficacy of methotrexate is nearly unsurpassed in the treatment of inflammatory arthritis. In another instance, a patient being treated for psoriasis was hospitalized and eventually died after taking methotrexate every 12 hours for 6 consecutive days instead of every 12 hours for 3 doses. Practical clinical pharmacology and drug interactions of low. Methotrexate mtx is an antimetabolic agent that affects the metabolism of folic acid. The treatment of this condition is primarily surgical, but medical management in. Methotrexate is used to treat leukemia and certain types of cancer of the breast, skin, head and neck, lung, or uterus. The results of this study suggest that auc mtx within the range of 2. Methotrexate has a large spectrum of potential drug interactions. Bc cancer protocol summary for central nervous system. Hodgkins lymphoma, osteogenic sarcoma, choriocarcinoma, breast. Prior to treatment with methotrexate injection usp, clinical and laboratory. Although methotrexate was first introduced as an antiproliferative agent that inhibits the synthesis of purines and pyrimidines for the therapy of malignancies, it is now clear that. Methotrexate is an antagonist of the enzyme dihydrofolate reductase, blocking the synthesis of tetrahydrofolate and therefore preventing the synthesis of purines and pyrimidines.
Methotrexate mtx is a folate analog widely used against a range of diseases including malignancies and autoimmune disorders. Important reminder at the end of this policy for important regulatory and legal information. Methotrexate also exhibits potent immunosuppressant activity although the mechanisms of. Molecular action of methotrexate in inflammatory diseases. Its mechanism of action, competitive inhibition of folatedependent steps in nucleic acid synthesis, effectively kills. Principles of clinical cancer chemotherapy and drug resistance cancer mortality. In the treatment of inflammatory autoimmune diseases, mtx is commonly administered orally as a single weekly.
Methotrexate mtx, a potent folate antagonist by virtue of its ability to inhibit. Antidotes to coumarins, isoniazid, methotrexate and. Methotrexate is an antimetabolite of the antifolate type. A possible influence on potential hepatotoxicity of an increase of c max for methotrexate cannot be excluded. Overall, these results indicate that the apparently increased risk for developing hepatotoxic reactions during coadministration of methotrexate and etretinate cannot be explained by drug accumulation due to pharmacokinetic interaction.
Methotrexate mtx, a potent folate antagonist by virtue of its ability to inhibit the enzyme dihydrofolate reductase 1, continues to be a useful cancer chemotherapeutic agent 2. Abstract methotrexate is now used widely for the treatment of acute leukemia, non. Clinical pharmacokinetics of methotrexate springerlink. The points discussed are as follows, a the bioavailability of oral preparations of mtx is approximately 1520% lower than that of intramuscular or intravenous mtx, although there is great variability in relative bioavailability. Discuss conventional and investigational treatment approaches to high. Methotrexate preservativefree vial clinical pharmacology. After a treatmentfree period of six months, he had selfmedication of mtx along with analgesic for joint pain for one week which followed ulceration of the.
It evaluate the pharmacological action of drug preferred route. The goal of this pilot study was to determine whether total or individual methotrexate glutamate levels mtxglu n in red blood cells correlate with disease activity and adverse events in crohns disease. Oct 28, 2020 based on published reports and its mechanism of action see clinical pharmacology 12. Pdf methotrexate mtx is an antimetabolic agent that affects the metabolism of folic acid. Pharmacology is a medical science that forms a backbone of the medical profession as drugs form the corner. Topical methotrexate therapy for psoriasis jama dermatology. Pdf katzung basic and clinical pharmacology 14th edition. The mean methotrexate halflife was prolonged when nsaids were coadministered 1. A textbook of clinical pharmacology and therapeutics. Katzung basic and clinical pharmacology 14th edition c2018 txtbk. The pharmacology behind medical treatment for ectopic pregnancy. Methotrexate elimination is reduced in patients with impaired renal functions. The pharmacology of methotrexate journal of the american.
The drug entered clinical medicine as an innovative antineoplastic drug in 1948, after the detection of its. Dec, 2012 the plasma clearance of methotrexate following small clinical doses is about 80mlmin, but may become saturated at high doses 20g. During 4 hr of hemoperfusion the plasma concentration of methotrexate fell from 5. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. The plasma clearance of methotrexate following small clinical doses is about 80mlmin, but may become saturated at high doses 20g. Gibson american society for clinical pharmacology and. Methotrexate binds to and inhibits the enzyme dihydrofolate reductase, resulting in inhibition of purine nucleotide and thymidylate synthesis and, subsequently, inhibition of dna and rna syntheses. It is used to treat cancer, autoimmune diseases, ectopic pregnancy, and for medical abortions. The major impact of methotrexate is therefore on more rapidly dividing cell systems, typically the gut lining and bone marrow. Methotrexate mtx, a classical antifolate, is one of the most widely used and studied anticancer agents 14.
Previously established as a chemotherapeutic agent for decades, methotrexate has been adapted for use as a medical therapy for unruptured ectopic pregnancies. T2 the pharmacology behind medical treatment for ectopic pregnancy. Clinical pharmacology of intermediatedose oral methotrexate. Fingerprint dive into the research topics of methotrexate. In conclusion, a strong correlation was observed between methotrexate pharmacokinetics auc mtx and its antipsoriatic effect pasi. The aim of this study was to evaluate its safety in elderly patients with rheumatoid arthritis. Clinical pharmacology is the science of drug use in humans. New laboratory method has a higher limit of detection and inaccuracies have been reported with methotrexate levels below 0. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of onecarbon groups in the synthesis of purine nucleotides and thymidylate. The clinical pharmacology of methotrexate new applications of an old drug.
Understanding the mechanisms of action of methotrexate. Clinical pharmacology of methotrexate bertino 1982. Practical clinical pharmacology and drug interactions of. Methotrexate otrexup, rasuvo, xatmep, reditrex reference number. Unlike other anticancer agents, mtx can be safely administered over a wide dose range, ranging from 20 mgm 2 per week in maintenance chemotherapy for acute lymphoblastic leukemia and treatment of nononcologic diseases including rheumatoid arthritis or psoriasis 4. Clinicians of all specialties prescribe drugs on a daily basis, and this is both one of the most useful but also one of the most dangerous activities of our professional lives. Dosing is routinely adjusted for body surface area bsa, but limited data describe the pharmacokinetics of hdmtx, particularly in obese andor. Safety of low dose methotrexate in elderly patients with. The clinical pharmacology of intermediatedose oral methotrexate mtx was studied in nine patients receiving 18 courses of treatment.
Ectopic pregnancy ep is a major cause of maternal morbidity and mortality. The recent dramatic intensification of methotrexate therapy can be attributed in part to advances in our understanding of the clinical pharmacology of the folate antagonists, as well as to the combination of positive results and their effective dissemination to medical oncologists. Its mechanism of action, competitive inhibition of folatedependent steps in nucleic acid synthesis, effectively kills the rapidly dividing ectopic trophoblast. Methotrexate is an antimetabolite and antifolate agent with antineoplastic and immunosuppressant activities. Sodium hydroxide and, if necessary, hydrochloric acid are added to adjust the ph to approximately 8. The aim of this study was to evaluate hdmtx disposition in these children to provide a rational basis for mtx dosing.
Pharmacokinetics of methotrexate huffman 1973 clinical. Methotrexate, poisoning, toxicity, overdose, folinic acid, leucovorin. Methotrexate otrexup, rasuvo, xatmep reference number. Therefore, methotrexate interferes with dna synthesis, repair, and cellular replication. Neal flomenberg, in pharmacology and therapeutics, 2009. Accp journals american college of clinical pharmacology. Describe the current incidence and presentation of high. It is thought to affect cancer and rheumatoid arthritis by two different pathways. Methotrexate is an efficacious immunosuppressant for induction and maintenance of remission in crohns disease. Information not only on its mechanism of action, but also its pharmacology has led to improved dosage schedules of this drug alone and in combination. The clinical pharmacology of methotrexate has not been well studied in older individuals.
The pharmacology and clinical use of methotrexate research. In 1 case, a 20yearold patient with renal failure died within 2 weeks after taking methotrexate that a pharmacist dispensed instead of metolazone. Clinical pharmacology of oral intermediatedose methotrexate. On the other hand, although mtx has an excellent pharmacological efficacy, mtx associated side effects in clinical use, which vary from patient to patient, are nonnegligible. Pancytopenia after treatment of keratoacanthoma by single. Weekly low dose methotrexate is an established treatment for rheumatoid arthritis, but its use in elderly people has not been adequately examined. Serum and urine mtx concentrations were measured by means of a competitive protein binding assay after oral aqueous solution 3 courses, 50mg tablets courses or iv drug 2 courses had been administered in four doses of 100 mgm2 at 6h intervals or in. Following the intravenous administration of 30 mg methotrexate mtx per square meter, the plasma disappearance was triphasic with half. Pdf methotrexate is now used widely for the treatment of acute leukemia, nonhodgkins lymphoma, osteogenic sarcoma, choriocarcinoma, breast. Pdf methotrexate is now used widely for the treatment of acute leukemia, non hodgkins lymphoma, osteogenic sarcoma, choriocarcinoma, breast. Curative acute lymphocytic leukemia, hodgkins disease, diffuse histiocytic lymphoma, burkitts lymphoma testicular cancer, choriocarcinoma. Due to diminished hepatic and renal function, as well as decreased folate stores in this population, relatively low doses should be considered, and these patients should be closely monitored for early signs of toxicity. From the clinical pharmacology branch, division of cancer treatment, national cancer institute, bldg.
Clinical pharmacology of methotrexate wiley online library. Clinical utility and pharmacology of highdose methotrexate in the treatment of primary cns lymphoma. Methotrexate mtx, formerly known as amethopterin, is a chemotherapy agent and immunesystem suppressant. Of 24 patients available for evaluation, who took 2. The absorption of methotrexate following intramuscular injection and oral administration of small doses 30mgm2 is rapid and complete. At lower doses than used for treatment of cancer, methotrexate also inhibits multiple enzymes involved in the synthesis of nucleotides, including aminoimidazole carboxamide ribonucleotide transformylase aicart. The clinical pharmacology of methotrexate has not been well studied in older. Dec 12, 2020 nearly all international regimens for pediatric acute lymphoblastic leukemia all incorporate intravenous high. The drug entered clinical medicine as an innovative. However, there was wide variation in the effects of. Sep 08, 2020 methotrexate interferes with the growth of certain cells of the body, especially cells that reproduce quickly, such as cancer cells, bone marrow cells, and skin cells. Drugs were applied twice a day for six weeks, and lesions were scored weekly for erythema, scale, and elevation. Plasma methotrexate clearance decreased from 79 mllmin 30 min into hemoperfusion to 28 mllmin at the conclusion.
Methotrexate errors clinical pharmacy and pharmacology. Harvardmit division of health sciences and technology 151 of. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Methotrexate is transported across cellular membranes via a carriermediated active type process. In vitro clearance of methotrexate by 17 artificial kidneys. Update on pharmacology, clinical uses and warning gathered the latest evidences about one of most important immunosuppressive drugs, methotrexate, aiming to. During high dose infusions, the peak plasma level is proportional to doses up to 200mgkg. For cancer, methotrexate competitively inhibits dihydrofolate reductase dhfr, an enzyme that participates in the tetrahydrofolate synthesis. After hemoperfusion methotrexate concentration increased as a consequence of multicompartmental pharmacokinetics to 5. Understanding and managing methotrexate nephrotoxicity. Discussion here is limited to medications that are likely to be used concomitantly with methotrexate in its short administration period from transplant to day 11.
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