7-hydroxymethotrexate and Psoriasis

The clinical pharmacokinetics of methotrexate, particularly when the drug is used at low doses for nonmalignant disease, are complicated and require extensive study. Bioavailability of the drug may be influenced--at least in part--by food intake. Biliary excretion can compensate for decreased renal excretion of methotrexate to some degree. However, further studies of the renal excretion of methotrexate are needed.

Topics: Animals; Arthritis, Rheumatoid; Bile; Biological Availability; Brain; Breast Neoplasms; Cell Line; Half-Life; Humans; Intestinal Absorption; Kidney; Kinetics; Liver; Metabolic Clearance Rate; Methotrexate; Neoplasms; Psoriasis; Tritium

The aim of this 13 week, randomized, parallel-group study was to evaluate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of low-dose intermittent oral methotrexate (LDMTX) in patients with psoriasis.. Twenty-four psoriatic patients (15 male and 9 female, aged 31-73 years) were given weekly doses of MTX doses of either 7.5 mg or 15 mg with each dose divided into three aliquots given at 12 h intervals. The pharmacokinetics of MTX were evaluated at weeks 1 and 13. Skin impairment was assessed using the PASI-scoring system (The Psoriasis Area and Severity Index) at baseline and at weeks 5, 9 and 13 of therapy. Haematological and biochemistry tests were also performed at these times.. The comparison of the areas under the plasma concentration-time curve (AUC(MTX)) after the first and third weekly doses showed that the extent of MTX accumulation in plasma was only about 12%. Two-way anova (factors: subject and the week of therapy) on the log-transformed AUC(MTX) showed no effect of the week of therapy (P>0.8). Moreover, the intraindividual variability in the AUC(MTX) was at least 4-fold less than the interindividual variability (F-test; P<0.01). The steady-state total plasma clearance of MTX ranged from 5.0 to 18.2 l h(-1) and was proportional to the renal clearance (r2=0.45, P<0.001) which accounted for 65+/-20% of the former. The renal clearance of 7-OHMTX was approximately 4-8% of that of the parent compound. PK/PD analysis revealed a highly significant inverse relationship between PASI (expressed as a percent of the initial value) and a steady-state AUC(MTX) (rs=-0.65, P<0.001). Seventeen subjects (8 from the 7.5 mg group and 9 from the 15 mg group MTX, P=0.67) achieved a greater than 50% decrease in the initial PASI score and were classified as responders. Thirteen of 14 subjects with AUC(24,36 h)> or =700 nmol l(-1) h responded to pharmacotherapy. Conversely, only 4 out of 10 subjects with AUC(24,36 h)<700 nmol l-1 h were responders (P<0.01, Fisher's exact test).. A strong correlation was observed between the pharmacokinetics (AUC(MTX) at the steady state) and antipsoriatic effect (PASI-score) of LDMTX. The considerable interindividual variability and low intraindividual variability in MTX pharmacokinetics support a role for therapeutic monitoring and dose individualization at the start of pharmacotherapy. The results of this study suggest that a steady state AUC(MTX) values of 700 nmol l(-1)h and higher are associated with a significantly better success rate of antipsoriatic therapy than lower values.

Topics: Adult; Aged; Dermatologic Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Methotrexate; Middle Aged; Prospective Studies; Psoriasis

The aim of this methodological study was to present and exemplify a system-approach-based technology in modeling the formation of the metabolite from the parent drug. To represent this process, the parent-metabolite dynamic system was defined in such a way that the concentration-time profile of the parent drug was considered the input, while the concentration-time profile of the metabolite the output, of this system. The system-approach-based modeling technology was used to determine the model of the parent-metabolite dynamic system and to obtain the model-based estimates of the rate of metabolite formation, the rate of metabolic ratio and the mean time of metabolite formation. The technology was applied to concentration data for methotrexate and 7-hydroxymethotrexate in patients with psoriasis after a single oral methotrexate dose. Third-order linear models were selected as optimal to approximate the parent-metabolite dynamic systems representing the formation of 7-hydroxymethotrexate from methotrexate of these patients. The model-based estimates of the metabolic ratios ranged from 0.53 to 0.95. The model-based estimates of the mean times of formation of 7-hydroxymethotrexate from methotrexate ranged from 9.13 to 25.13 h. The model-based estimates of the rates of formation of 7-hydroxymethotrexate from methotrexate reached peak values (ranging from 0.03 to 0.11 h-1) in the time interval 1.5-4.5 h after administration of methotraxate. This study does not only introduce the method that may be useful in gaining insight into metabolite formation, but also presents a new example of the methodological, conceptual and computational uniformity of the system-approach-based technology in modeling various biomedical systems.

Topics: Administration, Oral; Biological Availability; Biomedical Research; Chemistry, Pharmaceutical; Clinical Trials as Topic; Databases, Factual; Folic Acid Antagonists; Humans; Internet; Linear Models; Methotrexate; Models, Biological; Psoriasis; Software; Time Factors