Main Article Content
Methotrexate (MTX) is commonly used to treat rheumatoid arthritis. The drug is usually orally administered once a week. Due to the problems with saturation of absorption and gastrointestinal intolerance, twice weekly oral administration and once weekly subcutaneous administration regimens are also used in clinical practice. However, the effects of different oral dosing intervals on trough concentration at steady state (Ctr,ss) and efficacy of the drug have not yet been studied. Our objective was to compare the probability of target attainment (PTA) among three twice weekly oral MTX dosage regimens with different dosing intervals (Saturday morning- evening, Saturday-Sunday and Saturday-Tuesday). A Monte Carlo simulation for prediction of MTX-polyglutamates (MTX-PGs) concentrations in red blood cells (RBC) of simulated patients was conducted using a population pharmacokinetic model of MTX in rheumatoid arthritis patients. Percent PTA for RBC MTX-PGs Ctr,ss of ³ 83 nmol/L (the lower limit of the therapeutic range) was calculated for each MTX regimen. Our results based on Monte Carlo simulation showed that, at oral doses ³ 20 mg/week, twice weekly administration resulted in notably higher Ctr,ss of MTX-PGs and %PTA than those of once weekly regimen. No difference in %PTA among the three tested twice weekly oral dosage regimens was observed; therefore, dosing interval was unlikely to affect MTX efficacy for twice weekly regimens. Nonetheless, further clinical studies are required to verify this simulated observation.
Upon acceptance of an article, the Pharmacological and Therapeutic Society of Thailand will have exclusive right to publish and distribute the article in all forms and media and grant rights to others. Authors have rights to use and share their own published articles.
Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017 Jun;76(6):960-77.
Katchamart W, Narongroeknawin P, Chevaisrakul P, Dechanuwong P, Mahakkanukrauh A, Kasitanon N, et al. Evidence-based recommendations for the diagnosis and management of rheumatoid arthritis for non-rheumatologists: Integrating systematic literature research and expert opinion of the Thai Rheumatism Association. Int J Rheum Dis. 2017 Sep;20(9):1142-65.
Bannwarth B, Pehourcq F, Schaeverbeke T, Dehais J. Clinical pharmacokinetics of low-dose pulse methotrexate in rheumatoid arthritis. Clin Pharmacokinet. 1996 Mar;30(3):194-210.
Oguey D, Kolliker F, Gerber NJ, Reichen J. Effect of food on the bioavailability of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 1992 Jun;35(6):611-4.
Herman RA, Veng-Pedersen P, Hoffman J, Koehnke R, Furst DE. Pharmaco-kinetics of low-dose methotrexate in rheumatoid arthritis patients. J Pharm Sci. 1989 Feb;78(2):165-71.
Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses 15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014 Aug;73(8): 1549-51.
Zimmerman J. Methotrexate transport in the human intestine. Evidence for heterogeneity. Biochem Pharmacol. 1992 Jun 9;43(11):2377-83.
Korell J, Stamp LK, Barclay ML, Dalrymple JM, Drake J, Zhang M, et al. A population pharmacokinetic model for low-dose methotrexate and its poly-glutamated metabolites in red blood cells. Clin Pharmacokinet. 2013 Jun;52(6): 475-85.
Silva MF, Ribeiro C, Goncalves VMF, Tiritan ME, Lima A. Liquid chromato-graphic methods for the therapeutic drug monitoring of methotrexate as clinical decision support for personalized medicine: a brief review. Biomed Chromatogr. 2018 May;32(5):e4159.
Hendel J, Nyfors A. Nonlinear renal elimination kinetics of methotrexate due to saturation of renal tubular reabsorption. Eur J Clin Pharmacol. 1984;26(1):121-4.
Grim J, Chladek J, Martinkova J. Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases. Clin Pharmacokinet. 2003;42(2):139-51.
Dalrymple JM, Stamp LK, O'Donnell JL, Chapman PT, Zhang M, Barclay ML. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008 Nov;58(11):3299-308.
Takahashi C, Kaneko Y, Okano Y, Taguchi H, Oshima H, Izumi K, et al. Association of erythrocyte methotrexate-polyglutamate levels with the efficacy and hepatotoxicity of methotrexate in patients with rheumatoid arthritis: a 76-week prospective study. RMD Open. 2017 Jan 3;3(1):e000363.
Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol. 2004 Apr;31(4):645-8.
Braun J, Kastner P, Flaxenberg P, Wahrisch J, Hanke P, Demary W, et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008 Jan;58(1):73-81.
Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis. J Rheumatol. 2006 Mar;33(3):481-5.
Dhaon P, Das SK, Srivastava R, Agarwal G, Asthana A. Oral methotrexate in split dose weekly versus oral or parenteral methotrexate once weekly in rheumatoid arthritis: a short-term study. Int J Rheum Dis. 2018 May;21(5): 1010-7.
Pandya S, Aggarwal A, Misra R. Methotrexate twice weekly vs once weekly in rheumatoid arthritis: a pilot double-blind, controlled study. Rheumatol Int. 2002 May;22(1):1-4.
Pan S, Stamp LK, Duffull SB, Barclay ML, Dalrymple JM, Drake J, et al. Assessment of the relationship between methotrexate polyglutamates in red blood cells and clinical response in patients commencing methotrexate for rheumatoid arthritis. Clin Pharmacokinet. 2014 Dec;53(12):1161-70.