Background Although methotrexate (MTX) is the recognized cornerstone of rheumatoid arthritis (RA) therapy, the bioavailability (BA) of oral MTX may be compromised in doses greater than 15 mg/week. In contrast, parenteral MTX exhibits a dose-proportional increase in exposure throughout the dosing range, which may result in better efficacy.1 Parenteral MTX use is limited in clinical practice due to a lack of familiarity and availability, as well as challenges related to training for sterile self-injection techniques in patients with RA who have compromised manual dexterity. To address these issues, a single-use subcutaneous (SC) MTX auto-injector (MTXAI) was developed with 10-, 15-, 20-, and 25-mg doses to facilitate SC self-administration.
Objectives To compare the relative bioavailability of MTXAI with oral MTX and to demonstrate safety and tolerability of MTXAI in patients with RA.
Methods This was a 12-week, randomized, open-label, crossover study of 49 adult patients with RA in the US. MTX dose groups were chosen based on the patient’s current dose of MTX and disease control. Patients were assigned to 1 of 4 doses (10, 15, 20, or 25 mg). All received the dose of MTX via 1 of 3 randomly assigned (1:1:1) treatments: oral MTX, MTXAI (abdomen), and MTXAI (thigh). Pharmacokinetic (PK) blood samples were collected predose and at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 4, 6, 8, 10, and 12 hours postdose. Samples were analyzed by LC/MS. PK measures obtained included AUC, Cmax, and Tmax. Ratios for dose-normalized parameters were calculated.
Results Mean age was 61 years, 63% were female, and 90% were white. Patients had a mean body mass index of 30.7 kg/m2 and 13-year disease duration. PK analysis of MTXAI (thigh) vs. oral MTX showed that the BA of MTXAI was consistently greater at all dose levels (see figure). PK measures for MTXAI thigh and MTXAI abdomen were similar. Oral MTX exposure plateaued above 15 mg; however, no plateau was seen with MTXAI administration, which resulted in a higher exposure than the comparable oral dose. The relative BA (AUC of MTXAI vs. oral MTX) at 10, 15, 20, and 25 mg was 121%, 114%, 131%, and 141%, respectively. The ratio of the dose-normalized AUC (0-24 h) and Cmax of MTXAI vs. oral MTX was 127.61 (90% CI: 122.30-133.15) and 94.88 (90% CI: 87.95-102.37), respectively. There were 2 SAEs which were considered unrelated to treatment, including a death from a myocardial infarction in a 79-year-old man with a prior cardiac history. The treatments in both the MTX and MTXAI arms were otherwise generally safe and well tolerated.
Conclusions The bioavailability of oral MTX was found to be diminished at higher doses, which might limit its clinical utility. Patients on oral MTX who have had an inadequate clinical response may benefit from higher drug exposure levels by switching to MTXAI.
Furst DE, Koehnke R, Burmeister LF, et al. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. J Rheumatol. 1989;16(3):313-320.
Acknowledgements Editorial support provided by Connexion Healthcare (Newtown, PA).
Disclosure of Interest K. Dave Employee of: Antares Pharma, M. Schiff Consultant for: Antares Pharma, L. Simon Consultant for: Antares Pharma, J. Jaffe Employee of: Antares Pharma, B. Freundlich Shareholder of: Pfizer, Consultant for: Antares Pharma, Celgene, and BMS