Pharmacokinetic and Pharmacodynamic Evaluation of a Biosimilar Rituximab in Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) Treated with R-CHOP (Rituximab, Cyclophosphamide, Adriamycin, Vincristine, Prednisolone).
Authors: Viswabandya Auro , Prashanthi P.V. , Raju C. Nirmala , Rajsekhar Reena , Mathews Vikram , Madki Shivkumar , Abhayankar Dhiraj , Kethireddypally Rukmini , George Biju , Chandy Mammen , Reddy Cartikeya , Srivastava Alok 
Published: October 2019

Abstract
Addition of rituximab (375 mg/m2) to CHOP has been shown to improve survival in patients with DLBCL. However there is limited data on the pharmacokinetics (PK) and pharmacodynamics (PD) of this drug in this condition. We have evaluated the PK and PD of a biosimilar rituximab (Reditux®, Dr. Reddy’s Laboratories Ltd, Hyderabad, India) in 17 patients with newly diagnosed DLBCL treated at a single center with R-CHOP as part of a multi-center study undertaken to assess the safety and efficacy of this drug. R-CHOP (rituximab-375mg/m2; cyclophopsphamide-750mg/m2; adriamycin-50mg/m2; vincristine-1.4mg/m2 on day 1 and prednisolone-60mg/m2 on days 1 to 5) was given every 3 weeks for a total of 6 cycles. Blood samples for measurement of rituximab were collected just prior to start of infusion and 10min, 24, 72, 192 and 360 hours post-infusion for all patients during cycle 1 and in 6 patients during cycle 6 also. Additional samples were collected pre- and 10 minutes post-infusion after cycles 2, 3, 4, 5 and 6. Plasma rituximab levels were quantified using an immunoassay (sensitivity: 1ug/ml). B-lymphocyte counts were measured in peripheral blood samples taken from all patients at the beginning of each cycle. All patients were evaluated for clinical and radiological response after the 2nd, 4th and 6th cycles. Patients, mean age: 52 years (range:31–71) had disease in the following stages: stage II: 5, stage III: 7, stage IV: 5. Twelve out of 17 patients achieved complete remission while 5 had partial response (NCI criteria). At a mean follow-up of 5 months (range: 3–8), 3 patients had relapse of the disease. The arithmetic mean ±SD of PK parameters of Rituximab during cycle 1 were as follows: T½(hrs): 167±63; Cmax(ug/ml): 186±49; Cmin(ug/ml): 22.4±12.84; AUC0-∞ (ug.hrs/ml): 28162±11227) and Cl/F (ml/kg/hr): 23.8±10.8. These data are comparable with values previously reported for rituximab in other conditions. Though a 2–7 fold inter-individual variation was noted among these patients, there was no significant difference in these parameters between those in whom the disease relapsed as opposed to those who maintained remission. Among the 6 patients in whom data was available for the 1st and 6th cycles (table), there was significant reduction in Cl/F with associated increase in Cmax and AUC in the 6th cycle as compared to the 1st cycle. In 16 patients for whom the data was available, pre-treatment mean B lymphocyte count which was 121/ul (range:1.5–410.5) dropped to a mean of 9.9/ul (range:0.3–62.3) after the first cycle and remained in that range for the rest of treatment period. These data show that even with a 3-weekly regimen, therapeutic trough levels (25 μg/ml) of rituximab was observed across all cycles. In fact, the changing PK parameters of the drug with progressive cycles of R-CHOP suggest that fixed-dose regimens may not be the optimal way to administer this drug.
Parameter Cycle1 (n=6) Cycle 6 (n=6) p value T ½ (hours) 200 386 0.0481 Cmax (μg/ml) 203 279 0.0556 Cmin (360Hr) 24.71 82.16 0.0028 AUC0- ∞ (μg.hrs/ml) 31167 92240 0.0049 Cl/F(ml/kg/hr) 20.5 7.6 0.0030