Trimetrexate

369.4 g/mol

369.42

UPN4ITI8T4

249008

DTXSID3023714

C1314

P - Antiparasitic products, insecticides and repellents

118 Ų

2.55 (LogP)|2

215-217 °C

Tan colored solid; solubility in water: > 50 mg/ml /Trimetrexate D-glucuronate/|3.09e-02 g/L|Water 1 - 2 (mg/mL)|pH 4 Acetate buffer < 1 (mg/mL)|pH 9 Acetate buffer < 1 (mg/mL)|0.1NHC1 1 - 5 (mg/mL)|0.1 N NaOH < 1 (mg/mL)|Methanol 12 - 15 (mg/mL)|95% Ethanol 1 - 5 (mg/mL)|10% Ethanol 1 - 3 (mg/mL)|Dimethylacetamide 10 - 15 (mg/mL)|Dimethylsulfoxide approimately 100 (mg/mL)

8.0

Crystals from aqueous acetic acid; mp: 215-217 °C; poorly sol in water. /Trimetrexate monoacetate monohydrate/

Bulk: A sample stored at 60 °C for 30 days showed no decomposition (UV, HPLC). Solution: A solution in 5% methanol (0.5 mg/mL) showed no decomposition after 9 days (UV). A solution in 5% dimethylacetamide /pH 4 acetate buffer showed no decomposition after 48 hours(HPLC).

Trimetrexate is incompatible with solutions containing chloride ions. Only dextrose 5% in water is recommended for intravenous infusion.|Trimetrexate and leucovorin must be administered separately, as a precipitate forms instantly when these 2 drugs added together.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

The LD50 of intravenous trimetrexate in mice is 62 mg/kg (186 mg/m2). Myelosuppression is a dose-limiting toxic effect.

When given without leucovorin protection, trimetrexate therapy is associated with a moderate rate of serum enzyme elevations, serum ALT or AST elevations above 5 times ULN in up to 20% of patients. When given with leucovorin, however, trimetrexate has fewer side effects although serum enzyme elevations can still occur. In clinical trials in patients with HIV infection and Pneumocystis jirovecii pneumonia, ALT elevations above 5 times ULN occurred in 1% to 8% of patients, but were usually no more frequent than with standard therapy using trimethoprim with sulfamethoxazole. The elevations were typically transient, without accompanying symptoms or jaundice and resolved or improved despite continuation of therapy. No instances of clinically apparent acute liver injury attributed to trimetrexate have been reported in the literature. In addition, trimetrexate has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B. Nevertheless, trimetrexate probably has hepatotoxic potential, but because it has limited use, is given for short periods of time and is administered with leucovorin, it has not been convincingly linked to cases of clinically apparent liver injury with jaundice.

95% (over the concentration range of 18.75 to 1000 ng/mL)

For use, with concurrent leucovorin administration (leucovorin protection), as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Also used to treat several types of cancer including colon cancer.|FDA Label

Trimetrexate is a parenterally administered folate antagonist that is used as a second line therapy for severe Pneumocystis jirovecii (previously carinii) pneumonia. Trimetrexate therapy has been associated with transient, mild serum enzyme elevations during therapy, but has not been convincingly linked to instances of acute, clinically apparent liver injury.

Antineoplastic Agents

Antifungal Agents; Antimetabolites; Antimetabolites, Antineoplastic; Folic Acid Antagonists|Antineoplastic|Trimetrexate glucuronate is an investigational drug that is available for treatment use ... in a hospital setting in qualifying patients with Pneumocystis carinii pneumonia and who have exhibited serious ... intolerance to both co-trimoxazole and pentamidine. /Trimetrexate glucuronate/

Even though trimetrexate does not compete with the folate transport system for entry into cells, utilization of folates is reduced due to inhibition of dihydrofolate reductase. When trimetrexate is administered in high doses for the treatment of pneumocystis carinii pneumonia, leucovorin must be given concurrently with trimetrexate to reduce toxic effects on human tissues. It has been postulated that the absence of a folate transport system in pneumocystis carinii provides the opportunity for differential rescue of host tissue affecting antiprotozoal action.|Patients receiving trimetrexate should have frequent laboratory monitoring of hepatic and hematologic prameters, including serum alanine aminotransferase, serum aspartate aminotransferase, bilirubin, alkaline phosphatase, platelet count, and total and differential leukocyte counts. Although uncommon in AIDS patients receiving trimetrexate for pneumocystis carinii pneumonia, slight elevations of blood urea nitrogen and/or serum creatinine have been reported in patients receiving the drug for various cancers.|Isolated perfused rat liver has been used to study potential drug interactions with trimetrexate metabolism in vitro. Cimetidine, which inhibits oxidative drug metabolizing enzymes, decreased the clearance of trimetrexate to approximately one half of control values. Whether this occurs to a significant extent in vivo is unknown.

Trimetrexate, a non-classical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase (DHFR). During DNA synthesis and cellular reproduction, folic acid is reduced to tetrahydrofolic acid by the enzyme folic acid reductase. By interfering with the reduction of folic acid, trimetrexate interferes with tissue cell reproduction. Generally, the most sensitive cells to the antimetabolite effect of trimetrexate are those cells which are most actively proliferating such as malignant cells, dermal epithelium, buccal and intestinal mucosa, bone marrow, fetal cells, and cells of the urinary bladder. Because the proliferation of cells in malignant tissues is greater than in most normal tissues, trimetrexate may impair the growth of the malignant tissues without causing irreversible damage to normal tissues. Due to very serious and potentially life-threatening side-effects of this drug, leucovorin must be co-administered for at least 72 hours after the last dose.

Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033) (See all compounds classified as Folic Acid Antagonists.)|Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)|Antimetabolites that are useful in cancer chemotherapy. (See all compounds classified as Antimetabolites, Antineoplastic.)

Ten to 30% of the administered dose is excreted unchanged in the urine.|20 ± 8 L/m2|38 +/- 15 mL/min/m2 [patients with acquired immunodeficiency syndrome (AIDS) who had Pneumocystis carinii pneumonia (4 patients) or toxoplasmosis (2 patients). Trimetrexate was administered intravenously as a bolus injection at a dose of 30 mg/m2/day along with leucovorin 20 mg/m2 every 6 hours for 21 days]|Clinical pharmacokinetic studies in cancer patients show that trimetrexate plasma concentration-time curves are biphasic or triphasic in form. The terminal elimination half-life averages 13.6 hr. Mean total plasma clearance and volume of distribution as steady-state values were 27.9 ml/min/sq m and 21.1 l/sq m, respectively. Cerebrospinal fluid concentration was 3.4% of that in plasma, which shows that trimetrexate does not cross the blood-brain barrier well. Trimetrexate is 86 to 94% bound to plasma proteins.|Mean oral bioavailability of the parenteral solution (glucuronate) in AIDS patients was 42%, with a mean maximum plasma concentration of 1182 ng/ml (3.2 umole/l) achieved 1.8 hr postdose. /Trimetrexate glucuromate/

Hepatic. Preclinical data strongly suggest that the major metabolic pathway is oxidative O-demethylation, followed by conjugation to either glucuronide or the sulfate.|Trimetrexate is highly metabolized by the liver. At least 2 metabolites are excreted in urine. One metabolite has been identified a 4'-O-glucuronide conjugate of trimetrexate, which is formed as a result of oxidative O-dimethylation at the 4'-position and subsequent conjugation with glucuronic acid. About 15% of a dose is excreted in urine as unchanged trimetrexate, while another 20% apparently excreted as metabolites.

11 to 20 hours|The terminal elimination half-life averages 13.6 hours.

In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.|Trimetrexate binds to dihydrofolate reductase and prevents the conversion of dihydrofolate to biologically active tetrahydrofolate. It inhibits nucleic acid synthesis as a result of antithymidylate and antipurine effects.

Recommended method to remove /methotrexate/: charcoal hemoperfusion. /Methotrexate/|Leucovorin preferably should be given within the first hour after overdose; therefore, the initial route should be iv using a dose equal to amount of folic acid antagonist consumed. Thereafter, oral doses (15 mg) should be given every 6 hr for methotrexate. /Methotrexate/|Inadvertent intrathecal overdosage of methotrexate constitutes a medical emergency, requiring prompt treatment and management. Although data are limited, management may be guided by the dose administered, time elapsed since administration, and anticipated severity of neurotoxicity. Regardless of the dose administered, as soon as the overdose is recognized, a repeat lumbar puncture should be performed immediately and CSF allowed to drain to gravity. The efficacy of CSF drainage alone as a means for removing the drug is a function of the dose administered and time elapsed since administration, and decreases as these factors increase. If the dose exceeds 100 mg, prompt neurosurgical intervention with ventriculolumbar perfusion following immediate CSF drainage should be considered; continuous CSF drainage or multiple CSF exchanges may also be considered but are not likely to be as effective. Other treatment measures may include high-dose parenteral leucovorin calcium therapy to minimize systemic toxicity, corticosteroids to minimize CNS inflammatory reactions, and other supportive therapy as necessary. While the addition of leucovorin to the ventriculolumbar perfusion fluid has been suggested and employed, its value is not known and the possibility that it may be epileptogenic via this route of administration should be considered. The possible benefits of prophylactic anticonvulsant therapy are probably outweighed by the potential for obscuring acute neurologic symptoms and causing additional adverse effects. /Methotrexate/|In cases of overdosage of methotrexate, leucovorin calcium, a potent folic acid antagonist antidote, should be administered as soon as possible, preferably within the first hr. Use of leucovorin calcium after an hr's delay is much less effective. In general, the dose of leucovorin calcium should be equal to or greater than that of methotrexate. When large doses or overdoses of methotrexateare given, leucovorin calcium may be administered by iv infusion in doses up to 75 mg within 12 hr, followed by 12 mg im every 6 hr for 4 doses. Other leucovorin calcium dosage regimens are also recommended. When average doses of methotrexate appear to have an adverse effect, 6-12 mg of leucovorin calcium may be given im every 6 hr for 4 doses. Leucovorin calcium has been administered several hr following high-dose methotrexate therapy in an effort to control the duration of exposure of sensitive cells to methotrexate ("leucovorin rescue"); the manufacturers warn that this procedure is considered investigational and hazardous. /Methotrexate/

Side effects have been noted to occur less often with trimetrexate than with methotrexate. Hematologic toxicity has been the primary as well as the dose-limiting side effect seen to date in clinical studies in patients being treated for pneumocystis carinii pneumonia. These patients have had manageable decreases in neutrophil and platelet counts. Adverse effects reported in AIDS patients have included nausea, vomiting, diarrhea, reversible liver function abnormalities, skin rash, and fever. In cancer patients treated with trimetrexate (without leucovorin), hematologic toxicities have also been observed. Mild to moderate mucositis and stomatitis have occurred in some cancer patients, but this is rare in pneumocystis carinii pneumonia patients.

CI 898

Lipophilic dihydrofolate reductase structurally related to methotrexate, with antimicrobial and antitumor activity.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients