Scientific Information - ACR Poster #400, Philadelphia 2009

SWITCHING FROM ORAL TO PARENTERAL METHOTREXATE ADMINISTRATION PRODUCES CLINICAL IMPROVEMENTS THROUGH SELECTIVE ACCUMULATION OF LONG-CHAINS METHOTREXATE POLYGLUTAMATES
Joel M. Kremer, MD.¹, Rong Zablocki, MS² and Thierry Dervieux, PharmD².
1)Albany Medical College, Albany, NY; 2)Cypress Bioscience, Inc. San Diego, CA.
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Abstract

PURPOSE

Methotrexate (MTX) is effective in rheumatoid arthritis (RA), yet large interpatient variability in MTX absorption and activation to MTX polyglutamates (MTXPGs) often preclude the achievement of appropriate exposure to maximize antiarthritic effects. We evaluated the effects of switching from oral to parenteral MTX on disease activity and MTXPG accumulation in patients with RA.

METHODS

A total of 10 patients with RA taking oral MTX (dose 17.7±0.8 mg; average±SEM) for 27±3.0 weeks and presenting with a disease activity score (DAS28) of 4.3±0.4 were switched from oral to parenteral administration of MTX to control disease activity. In 4 patients, parenteral administration was also associated with an increase in MTX dose (final average dose 19.0±0.8 mg). At the time of the following visit (average 8.7±1.4 weeks later) DAS28 was determined together with MTXPG levels. Physicians were blinded to MTXPG concentrations. The intrapatient variability in RBC MTXPG levels was assessed in a total of 25 patients receiving a stable oral dose of MTX (range 7.5 to 20 mg/week) for at least 6-weeks. RBC MTXPG levels were determined twice, with the first determination made after 27 weeks (median) therapy (range 13-40 weeks) and the second determination made after 36 weeks (median) therapy (range 21-49 weeks). Long-chains RBC MTXPG3 were measured using liquid chromatography and the change in DAS28 and MTXPG levels between visits were assessed using Wilcoxon paired test or regression analysis.

RESULTS

The intrapatient variability (assessed using the coefficient of variation, CV) was low for MTXPG (median CV=10%) levels when patients were under a stable dose of oral MTX. Switching from oral to parenteral administration of MTX was associated with significant reduction in disease activity (median change -31%; p=0.004). In one patient the decrease in disease activity was only evident after 19 weeks of parenteral MTX. The change in MTX dosage was not associated with reduction in disease activity (p=0.39). In contrast, median percentage increase in RBC MTXPG levels before and after parenteral switch was 37% (range 6%-123%) (p=0.002). The percentage change in the disease activity score was associated with the absolute change in MTXPG levels (R2=0.50; p=0.022) thereby indicating that parenteral administration of MTX produced greater antiarthritic effects through greater accumulation of MTXPGs.

CONCLUSION

These data suggest that switching from oral to parenteral MTX administration produces clinical improvements through selective accumulation of long-chains MTXPGs and are consistent with the observation that parenteral administration is significantly more effective than oral administration (Arthritis Rheum. 2008 58:73-81).

To evaluate the effects of switching from oral to parenteral Methotrexate (MTX) on disease activity and Methotrexate Polyglutamates (MTXPGs) accumulation in patients with rheumatoid arthritis. We also sought to evaluate the intrapatient variability in MTXPG when the patient received a stable dose of MTX.

MTX Pharmacokinetics Vary Significantly Among Patients

Intrapatient variability in RBC MTXPG levels was assessed in a total of 25 patients receiving a stable oral dose of MTX (range 7.5 to 20 mg/week) for at least 6-weeks. RBC MTXPG levels were determined twice, with the first determination made after 27 weeks (median) therapy (range 13-40 weeks) and the second determination made after 36 weeks (median) therapy (range 21-49 weeks).
A total of 10 patients with RA under oral MTX (average dose 17.7±0.8 mg/week, average±SEM) for an average of 27±3.0 weeks (all patients started MTX at 7.5mg MTX at week 0, average±SEM) and presenting with disease activity scores (DAS-28) of 4.3±0.4 (average±SEM) were switched to parenteral administration of MTX (average dose 19.0±0.8 mg). In 4 patients, parenteral administration was also associated with an increase in MTX dose (median increase of 2.5 mg). At the time of the following visit (average 8.7±1.4 weeks later) disease activity score was determined together with MTXPG levels. In one patient the decrease in disease activity was only evident after 19 weeks of parenteral MTX (two visits after switching to parenteral administration).
RBC MTXPG levels were measured by liquid chromatography.
Statistical analysis consisted of Wilcoxon paired test or regression analysis.

Intrapatient variability at stable dose:

The intrapatient variability (assessed using the coefficient of variation, CV) was low for total MTXPG levels (median CV=8%, range 0-40%), and for MTXPG3 levels (median CV=10%, range 0-41%). However, MTXPG4-5 levels exhibited greater variability (median CV=22%, range 0-141%).

Effect of parenteral vs. oral administration:

The Figure indicates that switching to parenteral administration of MTX resulted in significant reduction in DAS-28 (median -31%; range 5% to -72%; p=0.004).

The change in MTX dosage was not associated with reduction in disease activity (p=0.39).

Median percentage increase in long-chain MTXPG3 levels before and after parenteral switch was 37% (range 6%-123%) (p=0.002).

Similarly, MTXPG4-5 levels increased (p=0.016), and became detectable in two of three patients. A median 132% increase (range 4%-395%) occurred in the 7 patients presenting with detectable MTXPG4-5 at baseline.

The percentage change in the DAS-28 was associated with the absolute change in MTXPG3 (R2=0.50; p=0.022) and MTXPG4-5 levels (R2=0.45; p=0.033) thereby indicating that the parenteral administration of MTX produced greater antiarthritic effects through greater accumulation of MTXPGs.

Switching from oral to parenteral MTX administration produces clinical improvements through selective accumulation of long-chains MTXPGs. These data are consistent with the observation that parenteral administration is significantly more effective than oral administration (Arthritis Rheum. 2008 58:73-81).