Real-world outcomes of diffuse large B-cell lymphoma in the biosimilar era.

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma (NHL). The clinical use of rituximab has improved the treatment response and survival of patients with DLBCL. The introduction of rituximab biosimilar into healthcare system has helped in providing a cost-effective treatment to B-cell lymphoid malignancies as standard of care and has improved access to patients worldwide. The aim of this study was to observe the real-world effectiveness and safety of Reditux™ and Ristova® in DLBCL patients. Methods: Observational study in adults with DLBCL receiving Reditux™ or Ristova® across 29 centers in India (2015-2022). Effectiveness and safety were assessed up to 2 years after first dose. Results: Out of 1,365 patients considered for analysis, 1,250 (91.6%) were treated with Reditux™ and 115 (8.42%) with Ristova®. At 2 years, progression-free survival (PFS) 69% [hazard ratio (HR), 1.16; 95% CI, 0.80-1.67], overall survival (OS) 78.7% (HR, 1.20; 95% CI, 0.78-1.86), response rates, quality of life (QoL), and overall safety in both the cohorts were comparable. The best overall response rate (BORR) at 6 months was comparable with no statistically significant differences between the Reditux™ and the Ristova® cohorts (89.2% vs. 94.3%). In multivariate analysis, BCL-2 and VAS were significant prognostic factors for PFS. Conclusion: Reditux™ and Ristova® were comparable in real-world setting. Clinical Trial Registration: ISRCTN registry, identifier (ISRCTN13301166).

Pharmacokinetic Similarity and Comparative Pharmacodynamics, Safety, Efficacy, and Immunogenicity of DRL_RI Versus Reference Rituximab in Biologics-Naïve Patients with Moderate-to-Severe Rheumatoid Arthritis: A Double-Blind, Randomized, Three-Arm Study.

OBJECTIVES: The aims were to demonstrate pharmacokinetic (PK) similarity between DRL_RI, a proposed rituximab biosimilar, and two reference innovator products (Rituxan® [RTX-US] and MabThera® [RTX-EU]) and compare their pharmacodynamics (PD), efficacy, safety, and immunogenicity in rheumatoid arthritis (RA) patients with inadequate response to methotrexate (MTX)-based therapy and no prior biologic administration. METHODS: In this randomized, double-blind, parallel-group study, 276 patients with moderate-to-severe active RA were randomized to receive DRL_RI, RTX-US, or RTX-EU on days 1 and 15. The primary PK end points included area under the concentration-time curve from time 0 to 336 h after first infusion (AUC0-14 days, first infusion), AUC from day 1 through week 16 (AUC0-∞, entire course), and AUC from time 0 to time of last quantifiable concentration after the second dose (AUC0-t, second infusion). Secondary end points included other PK parameters, such as maximum concentration (Cmax), time to Cmax after each infusion, terminal half-life, systemic clearance, and volume of distribution after the second infusion; PD parameters and efficacy until week 24; safety and immunogenicity at week 24 and 52; and B cell recovery until week 52. AUC from time 0 to time of last quantifiable concentration after the first dose and over the entire course from day 1 through week 16 (AUC0-t, entire course) was analyzed as an exploratory end point. RESULTS: The 91% confidence intervals (CIs) of the geometric mean ratios (GMRs) for the primary end point of AUC0-∞, entire course were within the bioequivalence limits of 80-125% for all comparisons: DRL_RI versus RTX-US 100.37% (92.30-109.14), DRL_RI versus RTX-EU 93.58% (85.98-101.85), and RTX-US versus RTX-EU 93.24% (85.62-101.54). PD outcomes (peripheral blood B-cell depletion and mean change in Disease Activity Score [28 joints]-C-reactive protein), efficacy, safety, and immunogenicity were also comparable between DRL_RI and the reference products. CONCLUSION: DRL_RI, a proposed biosimilar, demonstrated three-way PK similarity with RTX-EU and RTX-US, the reference innovator products, with comparable efficacy, PD, safety, and immunogenicity. CLINICAL TRIALS REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02296775.

Randomized, Double-Blind, Pharmacokinetic Equivalence Trial Comparing DRL-Rituximab With MabThera in Patients With Diffuse Large B-Cell Lymphoma.

PURPOSE: We sought to compare the pharmacokinetics (PKs) of DRL-rituximab (DRL_RI; potential biosimilar) and innovator rituximab MabThera (Roche, Grenzach-Wyhlen, Germany; reference medicinal product [RMP]) in patients with diffuse large B-cell lymphoma (DLBCL). Efficacy, pharmacodynamics (PDs), safety, and immunogenicity were also compared. PATIENTS AND METHODS: We conducted a double-blind, parallel-group study in patients with untreated DLBCL who were eligible to receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Patients were randomly assigned at a one-to-one ratio to receive DRL_RI or RMP for six 21-day cycles of rituximab plus CHOP, with 18 months of follow-up after day 1, cycle 6 (C6). Primary end point was C1 PKs, measured as area under the plasma concentration-time curve from day 0 to 21 (AUC0-21 days) and maximum plasma concentration (Cmax). Equivalence was defined as 90% CIs for the DRL_RI/RMP geometric mean ratios (GMRs) within 80% and 125%. Secondary end points included efficacy noninferiority measured by objective response rate (ORR) at C6 and event-free survival and overall survival at 87 weeks, PK equivalence at C6 and PD equivalence (rate of B-cell depletion and repletion), safety, and immunogenicity. The trial was stopped after sufficient patients for primary end point evaluation were enrolled. Secondary end points are reported as observed. RESULTS: A total of 151 patients were randomly assigned (DRL_RI, n = 76; RMP, n = 75). DRL_RI/RMP GMRs for AUC0-21 days and Cmax in C1 were 99.77 (90% CI, 87.60 to 113.63) and 96.19 (90% CI, 88.65 to 104.38), respectively. ORR at C6 for DRL_RI and RMP were 82.0% and 84.8%, respectively. Rates of B-cell depletion/repletion, immunogenicity, and adverse events were comparable in both groups. CONCLUSION: DRL_RI and RMP had equivalent PKs, with comparable efficacy, PDs, safety, and immunogenicity.

Sensitivity of Pegfilgrastim Pharmacokinetic and Pharmacodynamic Parameters to Product Differences in Similarity Studies.

In this work, a previously developed pegfilgrastim (PG) population pharmacokinetic-pharmacodynamic (PKPD) model was used to evaluate potential factors of importance in the assessment of PG PK and PD similarity. Absolute neutrophil count (ANC) was the modelled PD variable. A two-way cross-over study was simulated where a reference PG and a potentially biosimilar test product were administered to healthy volunteers. Differences in delivered dose amounts or potency between the products were simulated. A different baseline absolute neutrophil count (ANC) was also considered. Additionally, the power to conclude PK or PD similarity based on areas under the PG concentration-time curve (AUC) and ANC-time curve (AUEC) were calculated. Delivered dose differences between the products led to a greater than dose proportional differences in AUC but not in AUEC, respectively. A 10% dose difference from a 6 mg dose resulted in 51% and 7% differences in AUC and AUEC, respectively. These differences were more pronounced with low baseline ANC. Potency differences up to 50% were not associated with large differences in either AUCs or AUECs. The power to conclude PK similarity was affected by the simulated dose difference; with a 4% dose difference from 6 mg the power was approximately 29% with 250 subjects. The power to conclude PD similarity was high for all delivered dose differences and sample sizes.

A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim.

Neutropenia and febrile neutropenia (FN) are serious side effects of cytotoxic chemotherapy which may be alleviated with the administration of recombinant granulocyte colony-stimulating factor (GCSF) derivatives, such as pegfilgrastim (PG) which increases absolute neutrophil count (ANC). In this work, a population pharmacokinetic-pharmacodynamic (PKPD) model was developed based on data obtained from healthy volunteers receiving multiple administrations of PG. The developed model was a bidirectional PKPD model, where PG stimulated the proliferation, maturation, and margination of neutrophils and where circulating neutrophils in turn increased the elimination of PG. Simulations from the developed model show disproportionate changes in response with changes in dose. A dose increase of 10% from the 6 mg therapeutic dose taken as a reference leads to area under the curve (AUC) increases of ~50 and ~5% for PK and PD, respectively. A full random effects covariate model showed that little of the parameter variability could be explained by sex, age, body size, and race. As a consequence, little of the secondary parameter variability (Cmax and AUC of PG and ANC) could be explained by these covariates.

A comparative pharmacokinetic study of DRL_BZ, a candidate biosimilar of bevacizumab, with Avastin® (EU and US) in healthy male subjects.

AIM: The aim of this study was to compare the pharmacokinetics (PK) of DRL_BZ with that of EU-approved (reference medicinal product; RMP) and US-licensed (reference product; RP) bevacizumab (Avastin® ) in healthy male subjects. METHODS: In this double-blind, parallel-group, Phase 1 study (BZ-01-001), men aged 20-45 years were randomized 1:1:1 to receive a single intravenous infusion of 1 mg kg-1 of bevacizumab as DRL_BZ, RMP or RP. A total of 149 subjects were randomized (DRL_BZ, 50; RMP, 50; RP, 49). Primary endpoints included maximum observed serum concentration (Cmax ), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinity (AUC(0-∞) ), and area under the concentration-time curve from time zero (pre-dose) to last quantifiable concentration (AUC(0-t) ). Secondary objectives were to compare the safety and immunogenicity of DRL_BZ with those of the reference products. RESULTS: Primary PK parameters were comparable across groups, and 90% confidence intervals for the geometric mean ratios of the primary PK endpoints were within the pre-specified equivalence margins (80-125%) for all pairwise comparisons (DRL_BZ vs. RMP, DRL_BZ vs. RP and RMP vs. RP). No deaths or serious adverse events were reported. Similar numbers of subjects reported similar numbers of treatment-emergent adverse events in the three treatment groups. One subject who received DRL_BZ had anti-drug antibodies at the Day 85 visit; however, no anti-drug antibodies were detected in this subject at the 12-month follow-up visit. CONCLUSIONS: PK, safety and immunogenicity of DRL_BZ were comparable to EU-approved and US-licensed bevacizumab in healthy male subjects.