METHOTREXATE, VIALS 10 Clinical Pharmacology

methotrexate, vials

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10.1 Mechanism of Action

Methotrexate is a folate antagonist. 

Methotrexate inhibits dihydrofolate reductase (DHFR), the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate must be regenerated via the DHFR-catalyzed reaction in order to maintain the intracellular pool of tetrahydrofolate one-carbon derivatives for both thymidylate and purine nucleotide biosynthesis. The inhibition of DHFR by folate antagonists (methotrexate) results in a deficiency in the cellular pools of thymidylate and purines and thus in a decrease in nucleic acid synthesis. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. 

Methotrexate is most active against rapidly multiplying cells, because its cytotoxic effects occur primarily during the S phase of the cell cycle. Since cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. As a result, actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to DHFR inhibition effects of methotrexate. 

The cytotoxicity of methotrexate results from three important actions: inhibition of DHFR, inhibition of thymidylate synthase, and alteration of the transport of reduced folates. The affinity of DHFR to methotrexate is far greater than its affinity for folic acid or dihydrofolic acid, therefore, large doses of folic acid given simultaneously will not reverse the effects of methotrexate. However, Leucovorin calcium, a derivative of tetrahydrofolic acid may block the effects of methotrexate if given shortly after the antineoplastic agent. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. 

The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamination of methotrexate. The actual mechanism of action is unknown.

Methotrexate has immunosuppressive activity. This may be a result of inhibition of lymphocyte multiplication. The mechanisms of action in the management of rheumatoid arthritis of the drug are not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects. 

In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. 

10.2 Pharmacodynamics

Methotrexate has immunosuppressive and/or anti-inflammatory effects. The pharmacodynamics of methotrexate show large interpatient variability regardless of the route of administration or disease being treated. 

10.3 Pharmacokinetics 

Absorption 

Methotrexate is generally completely absorbed following parenteral administration, and after intramuscular injection peak serum concentrations occur in 30 to 60 minutes. 

Distribution 

Methotrexate is widely distributed into body tissues with highest concentrations in the kidneys, gallbladder, spleen, liver and skin. Methotrexate in serum is approximately 50% protein-bound. 

After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier­-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein-bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. 

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally. High cerebrospinal fluid concentrations of the drug may be attained by intrathecal administration. 

Metabolism 

At low doses, methotrexate does not appear to undergo significant metabolism; following high-dose therapy after absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. 

These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate syntheses. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumours. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed.  Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. 

Elimination

 

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration.  Total clearance averages 12 L/h, but there is wide interindividual variation. Excretion of single daily doses occurs through the kidneys in amounts from 80% to 90% within 24 hours. Repeated daily doses result in more sustained serum levels and some retention of methotrexate over each 24-hour period, which may result in accumulation of the drug within the tissues. The liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally. High concentrations of the drug, when needed, may be attained by direct intrathecal administration. 

With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion. Non-linear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.

Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. 

The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing.  

Half-Life 

The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours. 

Special Populations and Conditions 

  • Pediatrics: In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours. 
  • Geriatrics: The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses (especially in RA and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity. 
  • Pregnancy and Breast-feeding: Methotrexate has been detected in human breast milk and is contraindicated during breast-feeding. The highest breast milk to plasma concentration ratio reached was 0.08:1. 
  • Hepatic Insufficiency: Hepatic excretion of methotrexate is a minor route of elimination. However, the liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. 
  • Renal Insufficiency Since the renal excretion of methotrexate is the primary route of elimination with 80% to 90% of the single daily doses of methotrexate excreted through the kidneys within 24 hours, methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions, thus in patients with renal impairment the health care provider may need to adjust the dose to prevent accumulation of drug.
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10 Clinical Pharmacology

10.1 Mechanism of Action

Methotrexate is a folate antagonist. 

Methotrexate inhibits dihydrofolate reductase (DHFR), the enzyme that reduces folic acid to tetrahydrofolic acid. Tetrahydrofolate must be regenerated via the DHFR-catalyzed reaction in order to maintain the intracellular pool of tetrahydrofolate one-carbon derivatives for both thymidylate and purine nucleotide biosynthesis. The inhibition of DHFR by folate antagonists (methotrexate) results in a deficiency in the cellular pools of thymidylate and purines and thus in a decrease in nucleic acid synthesis. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. 

Methotrexate is most active against rapidly multiplying cells, because its cytotoxic effects occur primarily during the S phase of the cell cycle. Since cellular proliferation in malignant tissues is greater than in most normal tissues, methotrexate may impair malignant growth without irreversible damage to normal tissues. As a result, actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to DHFR inhibition effects of methotrexate. 

The cytotoxicity of methotrexate results from three important actions: inhibition of DHFR, inhibition of thymidylate synthase, and alteration of the transport of reduced folates. The affinity of DHFR to methotrexate is far greater than its affinity for folic acid or dihydrofolic acid, therefore, large doses of folic acid given simultaneously will not reverse the effects of methotrexate. However, Leucovorin calcium, a derivative of tetrahydrofolic acid may block the effects of methotrexate if given shortly after the antineoplastic agent. Methotrexate in high doses, followed by leucovorin rescue, is used as a part of the treatment of patients with non-metastatic osteosarcoma. 

The original rationale for high-dose methotrexate therapy was based on the concept of selective rescue of normal tissues by leucovorin. More recent evidence suggests that high dose methotrexate may also overcome methotrexate resistance caused by impaired active transport, decreased affinity of dihydrofolic acid reductase for methotrexate, increased levels of dihydrofolic acid reductase resulting from gene amplification, or decreased polyglutamination of methotrexate. The actual mechanism of action is unknown.

Methotrexate has immunosuppressive activity. This may be a result of inhibition of lymphocyte multiplication. The mechanisms of action in the management of rheumatoid arthritis of the drug are not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effects. 

In psoriasis, the rate of production of epithelial cells in the skin is greatly increased over normal skin. This differential in proliferation rates is the basis for the use of methotrexate to control the psoriatic process. 

10.2 Pharmacodynamics

Methotrexate has immunosuppressive and/or anti-inflammatory effects. The pharmacodynamics of methotrexate show large interpatient variability regardless of the route of administration or disease being treated. 

10.3 Pharmacokinetics 

Absorption 

Methotrexate is generally completely absorbed following parenteral administration, and after intramuscular injection peak serum concentrations occur in 30 to 60 minutes. 

Distribution 

Methotrexate is widely distributed into body tissues with highest concentrations in the kidneys, gallbladder, spleen, liver and skin. Methotrexate in serum is approximately 50% protein-bound. 

After intravenous administration, the initial volume of distribution is approximately 0.18 L/kg (18% of body weight) and steady-state volume of distribution is approximately 0.4 to 0.8 L/kg (40% to 80% of body weight). Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier­-mediated active transport process. At serum concentrations greater than 100 micromolar, passive diffusion becomes a major pathway by which effective intracellular concentrations can be achieved. Methotrexate in serum is approximately 50% protein-bound. Laboratory studies demonstrate that it may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin. 

Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally. High cerebrospinal fluid concentrations of the drug may be attained by intrathecal administration. 

Metabolism 

At low doses, methotrexate does not appear to undergo significant metabolism; following high-dose therapy after absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated forms that can be converted back to methotrexate by hydrolase enzymes. 

These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate syntheses. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues and tumours. A small amount of metabolism to 7-hydroxymethotrexate may occur at doses commonly prescribed.  Accumulation of this metabolite may become significant at the high doses used in osteogenic sarcoma. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 fold lower than the parent compound. 

Elimination

 

Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration.  Total clearance averages 12 L/h, but there is wide interindividual variation. Excretion of single daily doses occurs through the kidneys in amounts from 80% to 90% within 24 hours. Repeated daily doses result in more sustained serum levels and some retention of methotrexate over each 24-hour period, which may result in accumulation of the drug within the tissues. The liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier in therapeutic amounts when given parenterally. High concentrations of the drug, when needed, may be attained by direct intrathecal administration. 

With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose. Enterohepatic recirculation of methotrexate has been proposed.

Renal excretion occurs by glomerular filtration and active tubular secretion. Non-linear elimination due to saturation of renal tubular reabsorption has been observed in psoriatic patients at doses between 7.5 and 30 mg. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that also undergo tubular secretion, can markedly increase methotrexate serum levels. Excellent correlation has been reported between methotrexate clearance and endogenous creatinine clearance.

Methotrexate clearance rates vary widely and are generally decreased at higher doses. Delayed drug clearance has been identified as one of the major factors responsible for methotrexate toxicity. It has been postulated that the toxicity of methotrexate for normal tissues is more dependent upon the duration of exposure to the drug rather than the peak level achieved. When a patient has delayed drug elimination due to compromised renal function, a third space effusion, or other causes, methotrexate serum concentrations may remain elevated for prolonged periods. 

The potential for toxicity from high-dose regimens or delayed excretion is reduced by the administration of leucovorin calcium during the final phase of methotrexate plasma elimination. Pharmacokinetic monitoring of methotrexate serum concentrations may help identify those patients at high risk for methotrexate toxicity and aid in proper adjustment of leucovorin dosing.  

Half-Life 

The terminal half-life reported for methotrexate is approximately 3 to 10 hours for patients receiving treatment for psoriasis, rheumatoid arthritis or low dose antineoplastic therapy (less than 30 mg/m2). For patients receiving high doses of methotrexate, the terminal half-life is 8 to 15 hours. 

Special Populations and Conditions 

  • Pediatrics: In pediatric patients receiving methotrexate for acute lymphocytic leukemia (6.3 to 30 mg/m2), the terminal half-life has been reported to range from 0.7 to 5.8 hours. 
  • Geriatrics: The clinical pharmacology of methotrexate has not been well studied in older individuals. Due to diminished hepatic and renal function as well as decreased folate stores in this population, relatively low doses (especially in RA and psoriasis indications) should be considered and these patients should be closely monitored for early signs of toxicity. 
  • Pregnancy and Breast-feeding: Methotrexate has been detected in human breast milk and is contraindicated during breast-feeding. The highest breast milk to plasma concentration ratio reached was 0.08:1. 
  • Hepatic Insufficiency: Hepatic excretion of methotrexate is a minor route of elimination. However, the liver cells appear to retain certain amounts of the drug for prolonged periods even after a single therapeutic dose. Special caution is indicated in the presence of pre-existing liver damage or impaired hepatic function. 
  • Renal Insufficiency Since the renal excretion of methotrexate is the primary route of elimination with 80% to 90% of the single daily doses of methotrexate excreted through the kidneys within 24 hours, methotrexate is retained in the presence of impaired renal function and may increase rapidly in the serum and in the tissue cells under such conditions, thus in patients with renal impairment the health care provider may need to adjust the dose to prevent accumulation of drug.

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