Alternative Routes of Administration

For the treatment of rheumatoid arthritis, infliximab is approved in combination with methotrexate for intravenous dosing at 3 mg/kg every 8 weeks. As an alternative to the intravenous dosing route, an experimental formulation for subcutaneous and intramuscular (i.m.) dosing was evaluated in RA patients who are refractory to methotrexate therapy in a phase I clinical study. Fifteen patients were randomized to receive s.c. doses at 0.5 mg/kg, 1.5 mg/kg and 3 mg/kg. After evaluation of the pharmacokinetic data from this group, a 100-mg s.c. dose was chosen to treat patients either s.c. at weeks 0,2 and 4, or after 3-mg/kg i.v. infusions ofRemi-cade at weeks 0 and 2 with s.c. injections at weeks 4, 6 and 8. Another group of patients received 100-mg i.m. injections at weeks 0, 2 and 4.

After a single s.c. injection at doses ranging from 0.5 to 3 mg/kg, the median half-life ranged from 8.0 to 8.4 days and the Cmax and AUC increased in a roughly dose-proportional manner across these dose groups. At day 7, a 6.7-fold higher Cmax and a 6.3-fold higher AUC were determined in the 3-mg/kg dose when compared to the 0.5-mg/kg group. Subjects receiving three doses of 100 mg s.c. every 4 weeks had trough concentrations of infliximab above or equal to 1 ^g/ml. Over 80% of subjects receiving multiple doses of 100 mg infliximab s.c. achieved an ACR20 response when evaluated 2 weeks after the last dose of infliximab. In contrast, the response to i.m. infliximab administration appeared to be delayed since at 2 weeks post-treatment ~57 % of patients achieved an ACR20 response, while at 4 weeks post-treatment 83 % or five out of six patients achieved an ACR20 response. Individual patients in this study achieved higher clinical responses even after a single s.c. administration, and the majority after multiple s.c. injections achieved an ACR50 response, as did about one-third of patients in the i.m. group.

Irrespective of s.c. or i.m. administration, 34 out of 43 patients experienced transient AEs of mild to moderate severity. This included ten subjects having mild to moderate infections. There were no serious injection site reactions. In addition, the humoral response to either route of administration was not suppressed.

Thus this exploratory study described alternative routes of administration for infliximab that resulted in trough levels above or equal to 1 ^g/ml at week 4, which is considered the serum concentration required to achieve a clinical response. However, this study is too small to draw general conclusions regarding safety or efficacy (Westhovens et al. 2006).

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