Pharmacokinetics and Safety of Three Formulations of Rituximab (CT-P10, US-sourced Innovator Rituximab and EU-sourced Innovator Rituximab) in Patients with Rheumatoid Arthritis: Results from Phase 3 Randomized Controlled Trial over 24 Weeks

초록

Pharmacokinetics and Safety of Three Formulations of Rituximab (CT-P10, US-sourced Innovator Rituximab and EU-sourced Innovator Rituximab) in Patients with Rheumatoid Arthritis: Result from Phase 3 Randomized Controlled Trial over 24 Weeks Background/Purpose : CT-P10 is a proposed biosimilar candidate of rituximab, and it has been concluded to be highly similar to the reference product in terms of analytical and functional characteristics and equivalent to EU-sourced innovator rituximab (EU-RTX) in pharmacokinetics (PK) in the patients with RA through phase 1 study.1 The similarity in terms of PK was tested among CT-P10 and two innovator rituximabs from the different manufacturing sources in RA patients. Methods : A total of 189 RA patients in PK analysis part from a randomized controlled phase 3 study (NCT02149121) was randomly assigned in 1:1:1 ratio to receive 2 infusions of 1,000 mg CT-P10, US-sourced innovator rituximab (US-RTX) or EU-RTX with a 2-week interval. The following PK parameters were coprimary endpoints: area under the serum concentration-time curve from time zero to the last measurable concentration (AUC0-last), AUC from time zero extrapolated to infinity (AUC0-inf) and maximum concentration after the second infusion (Cmax) of CT-P10, US-RTX or EU-RTX. Pharmacokinetic similarity is concluded if the 90% confidence interval (CI) for the ratio of geometric means in AUC0-last, AUC0-inf, and Cmax are entirely contained within the bounds of 80% and 125% for the following comparisons: CT-P10 vs US-RTX, CT-P10 vs EU-RTX, and US‑RTX vs EU-RTX. Results : The PK parameters among 3 treatment groups were highly similar (Table 1). The 90% CIs for the ratio of geometric means for coprimary endpoints fell within the PK equivalence margin of 80-125% indicating that drug exposures from CT-P10 are similar to those from both US-RTX and EU-RTX and also from US-RTX to those of EU-RTX (Table 2). The safety profiles among 3 treatment groups were generally similar. Adverse events (AEs) due to infusion related reaction were reported for 6 (9.4%), 4 (6.2%) and 12 (20.0%) patients in CT‑P10, US-RTX and EU-RTX, respectively. All these events were mild to moderate (grade 1 or 2) in intensity. Six patients were discontinued due to an AE (2 [3.1%], 3 [4.6%] and 1 [1.7%] patients in CT-P10, US-RTX and EU-RTX, respectively). No malignancy, progressive multifocal leukoencephalopathy, serious infection or death occurred in any of the treatment groups. Conclusion : Pharmacokinetic equivalence was demonstrated in terms of AUC0-last, AUC0-inf and Cmax in the comparisons of CT-P10 to US-RTX, CT-P10 to EU-RTX, and US-RTX to EU-RTX in RA patients. In addition, comparable safety profiles were observed among the 3 treatment groups. Reference 1. Yoo DH, et al. Arthritis Rheum 2013;65(Suppl 10): S736