AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Department of Pharmacology Faculty of Medicine Charles University Hradec Králové Czech Republic

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Hendel J, Nyfors A. Non-linear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol. 1984;26:121–124. PubMed

Van Dooren-Greebe JR, Kuipers ALA, Mulder JTh, De Boo Van de Kerkhof PCM. Methotrexate revisited. Effects of long-term treatment in psoriasis. Br J Dermatol. 1994;130:204–210. PubMed

Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J. Clinical pharmacokinetics of low-dose methotrexate in rheumatoid arthritis. Clin Pharmacokinet. 1996;30:194–210. PubMed

Songsiridej N, Furst DE. Methotrexate – the therapy rapidly acting drug. Baillieres Clin Rheumatol. 1990;4:575–593. PubMed

Tishler M, Caspi D, Yaron M. Methotrexate treatment of rheumatoid arthritis: is a fortnightly maintenance schedule enough? Ann Rheum Dis. 1992;51:1330–1331. PubMed PMC

Roenigk HH, Mailbach HI. In: Psoriasis. 3. Shalita AR, Norris DA, editors. Marcel Dekker Inc; 1992. pp. 609–629.

Bannwarth B, Labat L, Moride Y, Schaeverbeke T. Methotrexate in rheumatoid arthritis. An update. Drugs. 1994;47:25–50. PubMed

Chládek J, Martı´nková J, Šimková M, Vanìèková J, Koudelková V, No??ièková M. Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of disease. Eur J Clin Pharmacol. 1998;53:437–444. PubMed

Finlay AY, Khan GK, Luscombe DK, Salek MS. Validation of sickness impact profile and psoriasis disability index in psoriasis. Br J Dermatol. 1990;123:751–756. PubMed

Šalamoun J, František J. Determination of methotrexate and its metabolites 7-hydroxymethotrexate and 2,4 diamino-N10-methylpteroic acid in biological fluids by liquid chromatography with fluorimetric detection. J Chromatogr. 1986;378:173–181. PubMed

Sasaki K, Hosoya R, Wang YM, Raulston GL. Formation and disposition of 7-hydroxymethotrexate in rabbits. Biochem Pharmacol. 1983;32:503–507. PubMed

Beck O, Seideman P, Wennberg M, Peterson C. Trace analysis of methotrexate and 7-hydrozymethotrexate in human plasma and urine by a novel high-performance liquid chromatographic method. Ther Drug Monit. 1991;13:528–532. PubMed

Bologna C, Anaya JM, Bressolle F, Jorgensen C, Laric R, Sany J. Correlation between methotrexate pharmacokinetic parameters, and clinical and biological status in rheumatoid arthritis patients. Clin Exp Rheumatol. 1995;13:465–470. PubMed

Ahern M, Booth J, Loxton A, et al. Methotrexate kinetics in rheumatoid arthritis: is there an interaction with nonsteroidal anti-inflammatory drugs? J Rheumatol. 1988;15:1356–1360. PubMed

Lebbe C, Beyeler C, Gerber NJ, Reichen J. Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis. Ann Rheum Dis. 1994;53:475–477. PubMed PMC

Kremer JM, Petrillo GF, Hamilton RA. Pharmacokinetics and renal function in patients with rheumatoid arthritis receiving a standard dose of oral weekly methotrexate: association with significant decreases in creatinine clearance and renal clearance of the drug after 6 months of therapy. J Rheumatol. 1995;22:38–40. PubMed

Oguey D, Köllinker F, Gerber NJ, Reichen J. Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 1992;35:611–614. PubMed

Kamel RS, Al-Hakiem MH, Rademaker M, Thomas RHM, Munro DD. Pharmacokinetics of small doses of methotrexate in patients with psoriasis. Acta Derm Venerol (Stockh) 1987;68:267–270. PubMed

Herman RA, Veng-Pedersen P, Hoffman J, Koehnke R, Furst E. Pharmacokinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci. 1989;78:165–171. PubMed

Sinnett MJ, Groff GD, Raddatz A, Franck WA, Bertino JS. Methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol. 1989;16:745–748. PubMed

Stewart CF, Evans WE. Drug–drug interactions with antirheumatic agents. Review of selected clinically important interactions. J Rheumatol. 1990;17(Suppl 22):16–23. PubMed

Tracy TS, Worster T, Bradley JD, Greene PK, Brater DC. Methotrexate disposition following concomitant administration of ketoprofen, piroxicam and flubiprofen in patients with rheumatoid arthritis. Br J Clin Pharmacol. 1994;37:453–456. PubMed PMC

Godfrey C, Sweeney K, Miller K, Hammliton R, Kremer J. The population pharmacokinetics of long-term methotrexate in rheumatoid arthritis. Br J Clin Pharmacol. 1998;46:369–376. PubMed PMC

Shen DD, Azarnoff DL. Clinical pharmacokinetics of methotrexate. Clin Pharmacokinet. 1978;3:1–13. PubMed

Anaya JM, Fabre D, Bressolle F, et al. Effect of etodolac on methotrexate pharmacokinetics in patients with rheumatoid arthritis. J Rheumatol. 1994;21:203–208. PubMed

Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19:453–456. PubMed

Seideman P, Beck O, Eksborg S, Wennberg M. The pharmacokinetics of methotrexate and 7-hydroxy metabolite in patients with rheumatoid arthritis. Br J Clin Pharmacol. 1993;35:409–412. PubMed PMC

Combe B, Edno L, Lafforgue P, et al. Total and free methotrexate pharmacokinetics, with and without piroxicam, in rheumatoid arthritis patients. Br J Rheumatol. 1995;34:421–442. PubMed

Eksborg S, Albertioni F, Beck O, Peterson C, Seideman P. Methotrexate in rheumatoid arthritis – a limited sampling strategy for estimation of the area under the plasma concentration versus time curve. Ther Drug Monit. 1994;16:560–563. PubMed

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