Pharmacokinetic and Pharmacodynamic Properties of a Biosimilar Rituximab (Reditux®) Are Identical to the Innovator Brand MabThera®– Experience from a Tertiary Cancer Centre in Western India (2014)

Abstract Background: Rituximab is a chimeric IgG1 monoclonal antibody targeting the CD20 surface antigen on normal and neoplastic B cells. Its use in combination with chemotherapy in CD20 positive B cell lymphomas has translated into better progression free and disease free survival making its incorporation, a standard of care in treatment of these lymphomas. However, the benefits of this important molecule may not have been available to a majority of patient in the developing countries but for the emergence of biosimilars in the market. The lack of defined regulatory norms in approving biosimilars for patient care has left some doubts regarding their true efficacy in comparison to the innovator MabThera® (Roche). Although our clinical experience suggests comparable efficacy and safety for the biosimilar, we embarked on a formal pharmacokinetic study of the biosimilar, Reditux®, used in combination with standard CHOP or CHOP like regimen in patients with diffuse large B cell lymphoma planned for chemo-immunotherapy. We present our data on twenty-one prospectively treated patients and compared it with the published data on MabThera®. Methods: This was a prospective, single centre pharmacokinetic study conducted between Nov 2011 and June 2013. Patients diagnosed with DLBCL, and treated with Reditux® in combination with chemotherapy, were enrolled into the study. All patients received six cycles of R-CHOP, wherein they received 375mg/m2 Reditux as a graded infusion of 50mg, 100mg and maximum 200mg during the first, second and third hour respectively on day 1 of first cycle. The chemotherapy consisted of standard CHOP including cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 and vincristine 1.4 mg/m2 (for a maximum single dose of 2 mg), administered intravenously on day 1 after Rituximab infusion, along with 100 mg oral prednisone for 5 days from first day. Serial blood sampling was done during the first cycle of R-CHOP at pre-dose, immediately post infusion and thereafter at 24, 48, 144 hours post infusion with a last sample collected on day 21. The plasma level of rituximab was determined by ELISA (Life Technologies, USA) with a sensitivity of 50 ng/mL. Rituximab AUC and other pharmacokinetic parameters were calculated from the observed concentrations at each time point using WinNonlin® version 6.3. The peripheral blood B-cell count was done on day 3 and day 21 of chemoimmunotherapy. The absolute B cell percentage was calculated by flow-cytometry using CD45, CD19 and CD20. Influence of covariates on AUC of Reditux was analyzed by linear regression. Results: A total of 21 patients were enrolled into the study including 18 males and 3 females. The median age was 50 years in the Reditux® group (range 24-70). Four patients were above 60. Majority (n=12) had Stage 4 disease. The pharmacokinetic parameters described in the table were comparable with the pharmacokinetic profile of MabThera® from published literature. High inter patient variability in pharmacokinetics was observed (CV=88%). Age and gender did not influence pharmacokinetics of the biosimilar though the numbers are few to derive firm conclusions. The median B cell count on day 3 and day 21 of first cycle was 1.75 ± 0.27 and 5.56 ± 1.24 cells/µl respectively. Of the 21 patients, four were lost to follow up while 2 patients had progressive disease and died. At a median follow of 19 months 70.3% of patients from the Reditux® group were progression free. There was no untoward immediate or late toxicity attributable to Reditux® on follow up. Conclusions: Reditux® has similar pharmacokinetic profile as MabThera®. The B-cell kinetics following Reditux® administration are similar to that reported for MabThera®. This study gives further credence to Reditux® as a suitable alternative to MabThera®in the treatment of CD20 positive B cell lymphomas. Table: Pharmacokinetic parameters of Reditux® and Mabthera® PK parameter (mean ± SD) Reditux®(N=21) MabThera® (published literature) AUC (0-t) hr* µg / mL 54,236 ± 47,555 - C max (µg / mL ) 555.74 ± 141.46 408 Vd ( L) 1.3 ± 0.64 2.7 CL (l/day) 0.15 ± 0.16 0.14 Half life (days ) 10.9 ± 8.6 22 MRT last (days) 2.78 ± 3.08 - Vd=Volume of distribution, CL=Clearance, MRT=Mean Residence Time Disclosures No relevant conflicts of interest to declare.