Methotrexate (MTX) PDF

Folic acid anti-metabolite That competitively inhibits dihydrofolate reductase. Enzyme responsible for converting: folic acid to the reduced or active folate cofactors. neoplasms, leukemia, osteogenic sarcoma, Used to treat a number of: breast cancer, non-Hodgkin’s lymphoma. Oral , Parenteral pa...

Folic acid anti-metabolite That competitively inhibits dihydrofolate reductase. Enzyme responsible for converting: folic acid to the reduced or active folate cofactors. neoplasms, leukemia, osteogenic sarcoma, Used to treat a number of: breast cancer, non-Hodgkin’s lymphoma. Oral , Parenteral parenteral route when doses exceed 30 mg/m2 Administered by: If < 30 : Since absorption is limited in higher doses Intro: ► Oral absorption limited. ► Dosing regimens ( high dose administered over a period of 3-6 hours to 40 hours). 2.5 mg to 12 gm/m2 or more. ► Approximately 50% bound to plasma proteins. ► Weak acid. ► At low pH, limited solubility May precipitate in urine, ► Patient receiving high-dose methotrexate Causing renal damage should receive hydration. ► Urine pH should be maintained above 7. / Alkaline ♦ Some minor metabolites with weak activity, ♦ Most important 7-hydroxy- methotrexate. Concentration of this metabolite may become significant with high doses of methotrexate. Metabolites: 1/200th the clinical activity of methotrexate, ♦ 7-hydroxy- methotrexate has only about: ♦ One- third to one-fifth as soluble. ♦ May precipitate in renal tubules causing acute nephrotoxicity. Because of Solubility problems: To ensure that methotrexate toxicities do not occur in moderate and high-dose treatment in doses that range from 10 to 100 mg/m2. 1x10^-7 molar. • until the plasma concentration of methotrexate falls below the critical value of: ♦ Leucovorin administered every 4 to 6 hours • from 12 to 72 hours, or •increasing the leucovorin rescue dose to 50 to 100 mg/m2 >1x10-7 molar for >48 hours •Usual course of rescue therapy Plasma: Continuous CNS methotrexate concentrations following doses of <30mg/m2. At higher doses extent of absorption declines and bioavailability incomplete. moderate and high dose methotrexate regimens must be administered by: parenteral route. May be administered parenterally or orally. Bioavailability: For this reason: Low- dose methotrexate (<30 mg/m2) Relationship between methotrexate plasma concentrations and volume of distribution complex Bi-exponential elimination curve. Initial plasma volume of distribution : 0.2L/kg 0.5 to 1.0L/kg Second larger volume of distribution : following complete distribution. Multi-compartmental modeling, Variable relationship between plasma concentration and apparent volume of distribution of methotrexate , Volume of Distribution: These make calculation of methotrexate loading doses somewhat speculative. When loading doses are required a volume of distribution of 0.2 to 0.5 L/kg is usually employed. Presence of third space fluids such as ascites, edema, or pleural effusions influence the volume of distribution. Dose > 30mg/m2 (only parenteral) Vast majority eliminated by renal route. Ranges from 1 to 2 times the creatinine clearance. Clearance by active transport mechanism May be saturable Vi (initial): I Leucovorin rescue: Probenecid, Renal clearance influenced by a number of compounds: Sulfisoxazole - 100% F: •Primary goal of methotrexate plasma monitoring peak concentrations occur 1 to 2 hours >10-8 molar Dose < 30mg/m2 (can give by oral & Parentral) Key parameters: oral absorption complete and rapid, requires increased leucovorin rescue doses. >1x10-6 molar for> 48 hours •When methotrexate concentration exceeds 1x10-6 molar at 48 hours, •Ensure that all patients receive adequate doses of rescue factor to prevent serious toxicity. ♦ Urine alkalinized. Therapeutic plasma concentration-variable Toxic concentration CNS: or more reduces methotrexate toxicity. ♦ Patients receiving large doses of methotrexate should be adequately hydrated V (AUC): Cl: - variable 0.2 L/kg 0.7 L/kg [1.6][CLcr] αa (plasma concentration > 5x10-7 molar). 3 hours T 1/2: βb (plasma concentration < 5x10-7 molar) 10 hours Inhibit dihydrofolate reductase (DHFR) And ultimately to deplete the reduced folate cofactors Goal of therapy: ♦ Relative ability to inhibit DHFR ♦ Time course required to deplete the cofactors critical to relationship between drug’s efficacy and its toxicity. ♦ generally administered in mg or gm doses Notes: ♦ plasma concentrations reported in units of mg/L, μg/mL and molar or micro molar units. Methotrexate concentrations reported in molar units, 10^-8 to 10^-2 molar. To convert concentrations in units of mg/L to molar concentrations, Units: Methotrexate concentration in 10^-6 Molar = Methotrexate concentration in mg/L / 0.454 MOL. WEIGHT: 454 GM/MOLE The factor 0.454 is the number of mg/L equal to 10^-6 molar or 1 micro molar. 1. be converted to 10^-6 molar Methotrexate concentrations reported in molar units should: THERAPEUTIC AND TOXIC PLASMA CONCENTRATIONS: Most therapeutic regimens designed to achieve concentrations: 2. multiplied times the factor 0.454 to calculate the equivalent methotrexate concentration in units of mg/L: above (0.1 micromolar) for < 48 hours. = toxicity Concentrations associated with successful treatment of various neoplasms THERAPEUTIC PLASMA CONCENTRATIONS: ♦ adequate hydration and renal function are maintained and METHOTREXATE (MTX) These levels not usually associated with serious methotrexate toxicity as long as: ♦ methotrexate concentration falls below 1x10^-7 molar within 48 hours Salicylates Reason: methotrexate renal clearance may be inhibited TOXIC PLASMA CONCENTRATION: Clearance: ♦ Methotrexate Chemotherapeutic in cancer cells ♦ Folic acid deficiency within the cells and causing their demise. Changes in renal function important in: And monitoring methotrexate therapy ● Oral and gastrointestinal mucositis ● Acute hepatic dysfunction. •Methotrexate only 50% bound to plasma proteins. designing ● Myelosuppression, Most common toxic effects of methotrexate: •Salicylate-induced methotrexate toxicity •Plasma protein displacement of methotrexate, or discontinuation of leucovorin rescue Plasma concentrations exceeding 1x10^-7 molar for 48 hours or more All drugs should be added cautiously to the regimen of a patient Mechanism : Alteration in renal clearance. following the initiation of therapy ♦ Normal cells not immune from this effect of Methotrexate Plasma level and their renal function monitored. Low white blood counts Low platelet count Anemia Small percentage of methotrexate metabolized; Hair Loss Significant amounts of methotrexate metabolites can be found in urine when large doses are administered. 7-hydroxy-methotrexate compound, Cause significant side effects: Leucovorin Rescue for Methotrexate Toxicity: Most extensively studied metabolite Liver damage Potentially nephrotoxic because of its: low water solubility. Lung damage Nerve damage Kidney damage Relationship between methotrexate’s volume of distribution and clearance complex. ♦ Using Leucovorin capacity – limited intracellular transport and Prevented or treated: Potential for: = mean active capacity – limited renal clearance, changing volume of distribution Apparent half-lives for methotrexate determined by : changing clearance. HALF-LIFE(T1/2): Intravenous: 2 to 3 hours Appears to represent the elimination phase reasonably well. Dosage forms: Oral tablets: Initial α half- life : ♦Frequently used in conjunction with β or terminal half-life of approximately 10 hours Other note on Leucovorin: Mechanism of action: may indicate whether the elimination of methotrexate is normal. as opposed to 5-FU ♦ Binds to enzyme inside cancer cells (Thymidilate Synthetase) Two situations when monitoring methotrexate level for efficacy useful: ♦ Normally administered intravenous route. ♦ Life span in blood and body tissues very short TIME TO SAMPLE: ♦ Samples obtained 24 to 48 hours following the initiation of therapy ♦ Plasma samples obtained before the critical 48- hour time period ♦ Limited to minutes. Leucovorin enhances binding of 5-FU to enzyme When using methotrexate levels to evaluate the leucovorin rescue dosage regimen: ♦ Prolongs life span of 5-FU, greater anti cancer effect ► Very well tolerated Side effects of Leucovorin: Sometime during the IV infusion, At 48 hours, And then every 24 hours less than 1x10^-7 molar. ♦ Very different when combined with Methotrexate ♦ Exerts anti cancer effect on cells 5-FU and Leucovorin: or duration of administration. Methotrexate & 5-FU. ♦ an adjunct to these chemotherapy drugs. 1. Patients who are to receive prolonged (= higher) methotrexate infusions since the infusion rate can be adjusted. to determine whether additional leucovorin will be required either: used every six hours for 48 hours ♦ compound similar to Folic acid, which is a vital Vitamin. Determine if the quantity and/or duration of leucovorin rescue is adequate. in quantity immediate effect, severe Methotrexate toxicity ♦ not Chemotherapeutic drug itself, Plasma concentrations used to evaluate potential efficacy of a given dosing regimen 2. Patients who are going to receive repeated methotrexate doses in which case future doses can be adjusted (infusion rate) to achieve the desired target concent. ♦ Normally administered 24 hours after Methotrexate is given. ♦ Allows Methotrexate to exert its anti cancer effect. Elimination of methotrexate not accurately described by: linear pharmacokinetic model Soreness of the mouth, difficulty swallowing Diarrhea ► Almost no side effects. ► Used with 5-FU increase severity of side effects of that drug. Levels monitored: Until levels drop below the concentration at which the patient is considered to be ‘rescued’ usually to: Answer: Q.1: Calculations: Answer: Q.2: