Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases
Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX is individually highly variable, resulting in a different systemic exposure to the drug and a variable therapeutic/toxic effect in patients....
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Published in | Clinical pharmacokinetics Vol. 42; no. 2; pp. 139 - 151 |
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Format | Journal Article |
Language | English |
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Auckland
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2003
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Abstract | Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX is individually highly variable, resulting in a different systemic exposure to the drug and a variable therapeutic/toxic effect in patients. The improvements and exacerbations of disease activity in relation to the introductions and discontinuations of LDMTX therapy suggest the possible immunosuppresive and anti-inflammatory properties of the drug. Because of a strong correlation between the drug pharmacokinetics and the therapeutic outcomes (pharmacodynamics), it seems to be possible to individualise the LDMTX therapy according to the results of pharmacokinetic/pharmacodynamic analysis. In the case of psoriasis, pharmacokinetic/pharmacodynamic analysis in our local study revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC(MTX) (area under the curve of methotrexate plasma concentrations; r(8) = -0.65, p < 0.001). The considerable inter-individual variability and low intra-individual variability in MTX pharmacokinetics, supports a role for therapeutic monitoring and dose individualisation at the start of pharmacotherapy. The results of this study suggest that a steady-state AUC(MTX) value of 700 nmol x h/L and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values. The preliminary results in our follow-up study suggest the statistically higher incidence of unwanted effects depending on maximum plasma concentration of the drug. Moreover, statistically significant correlation was found between the toxic effects and exposure to the drug regarding methotrexate plasma concentrations and intracellular storage in erythrocytes. However, the data are still in the process of being completed and are not yet published. |
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AbstractList | Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX is individually highly variable, resulting in a different systemic exposure to the drug and a variable therapeutic/toxic effect in patients. The improvements and exacerbations of disease activity in relation to the introductions and discontinuations of LDMTX therapy suggest the possible immunosuppresive and anti-inflammatory properties of the drug. Because of a strong correlation between the drug pharmacokinetics and the therapeutic outcomes (pharmacodynamics), it seems to be possible to individualise the LDMTX therapy according to the results of pharmacokinetic/pharmacodynamic analysis. In the case of psoriasis, pharmacokinetic/pharmacodynamic analysis in our local study revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC(MTX) (area under the curve of methotrexate plasma concentrations; r(8) = -0.65, p < 0.001). The considerable inter-individual variability and low intra-individual variability in MTX pharmacokinetics, supports a role for therapeutic monitoring and dose individualisation at the start of pharmacotherapy. The results of this study suggest that a steady-state AUC(MTX) value of 700 nmol x h/L and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values. The preliminary results in our follow-up study suggest the statistically higher incidence of unwanted effects depending on maximum plasma concentration of the drug. Moreover, statistically significant correlation was found between the toxic effects and exposure to the drug regarding methotrexate plasma concentrations and intracellular storage in erythrocytes. However, the data are still in the process of being completed and are not yet published. |
Author | CHLADEK, Jaroslav MARTINKOVA, Jirina GRIM, Jiri |
Author_xml | – sequence: 1 givenname: Jiri surname: GRIM fullname: GRIM, Jiri organization: Department of Pharmacology, Charles University, Hradec Králové, Czech Republic – sequence: 2 givenname: Jaroslav surname: CHLADEK fullname: CHLADEK, Jaroslav organization: Department of Pharmacology, Charles University, Hradec Králové, Czech Republic – sequence: 3 givenname: Jirina surname: MARTINKOVA fullname: MARTINKOVA, Jirina organization: Department of Pharmacology, Charles University, Hradec Králové, Czech Republic |
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Keywords | Pharmacokinetic pharmacodynamic relationship Skin disease Toxicity Diseases of the osteoarticular system Autoimmune disease Inflammatory joint disease Folic acid Antifolate Therapeutic drug monitoring Absorption Methotrexate Human Immunopathology Psoriasis Low dose Elimination Oral administration Metabolism Biological activity Parenteral administration Chronic Antimetabolic Rheumatoid arthritis Interindividual comparison Pharmacokinetics |
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Snippet | Low dose pulse methotrexate (LDMTX) therapy has become effective in the treatment of autoimmune and lymphoproliferative diseases. The pharmacokinetics of LDMTX... |
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SubjectTerms | Animals Antidotes - therapeutic use Antimetabolites - adverse effects Antimetabolites - pharmacokinetics Antimetabolites - therapeutic use Biological and medical sciences Folic Acid - therapeutic use Humans Immunomodulators Intestinal Absorption Leucovorin - therapeutic use Medical sciences Methotrexate - adverse effects Methotrexate - pharmacokinetics Methotrexate - therapeutic use Pharmacology. Drug treatments |
Title | Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases |
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