Retifanlimab is an immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed death receptor-1 (PD-1) and blocks its interaction with its ligands PD-L1 and PD-L2. Engagement of PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may be expressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of T-cell function such as proliferation, cytokine secretion and cytotoxic activity. Retifanlimab binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2, and potentiates T-cell activity.
Anti-drug antibodies (ADA) were uncommonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
The pharmacokinetics (PK) of retifanlimab were characterised using a population pharmacokinetics analysis with concentration data collected from 634 patients with various cancers who received retifanlimab doses of 1, 3, 10 mg/kg every 2 weeks, 375 mg every 3 weeks, or 3 mg/kg, 10 mg/kg, 500 mg and 750 mg every 4 weeks. The AUC was dose proportional in the studied dose range. The geometric mean (CV%) of Cmax and AUC at steady state for the recommended 500 mg every 4 weeks dose were 193 mg/L (24.1%) and 2190 day*mg/L (32.4%).
The geometric mean value (CV%) for volume of distribution at steady state is 6.1 L (20.2%).
The metabolic route of retifanlimab has not been characterised. Retifanlimab is expected to be catabolised through protein degradation processes.
A geometric mean (CV%) clearance of 0.314 L/day (36%), without accounting for the time-varying part of the clearance, with a half-life of 14.6 days (31.5%) and 18.7 days (28.7%), after first-dose and at steady-state, respectively, were estimated in the population pharmacokinetic analyses.
The following factors are not expected to have clinically important effects on the pharmacokinetics of retifanlimab: age (range: 18 to 94 years), weight (35 to 133 kg), sex, race, or tumour burden.
The effect of renal impairment on the clearance of retifanlimab was evaluated by population pharmacokinetic analyses in patients with mild (n=277) or moderate (n=142) renal impairment (eGFR between 89 and 30 mL/min/1.73m²; n=419) compared to patients with normal renal function (eGFR ≥90 mL/min/1.73m²; n=200). No clinically important differences were found in the clearance of retifanlimab. There are limited data in patients with severe renal impairment (n=4, lowest eGFR 26.0 mL/min/1.73m²). Retifanlimab has not been studied in patients with end-stage renal disease.
The effect of hepatic impairment on the clearance of retifanlimab was evaluated by population pharmacokinetic analyses in patients with mild (n=78; TB > ULN to 1.5 ULN or AST > ULN) hepatic impairment compared to patients with normal (n=555; TB and AST ≤ ULN) hepatic function. No clinically important differences were found in the clearance of retifanlimab. There are limited data in patients with moderate (n=1; TB between 1.5 and 3.0 times ULN and any AST) hepatic impairment. Retifanlimab has not been studied in patients with severe (TB between 3.0 and 10 times ULN and any AST) hepatic impairment.
No findings of toxicological significance were observed in monkeys in studies of up to 13 weeks duration at exposures sufficiently in excess compared to the clinical exposure at the recommended dose of 500 mg retifanlimab every 4 weeks.
No studies have been performed to assess the potential of retifanlimab for carcinogenicity or genotoxicity.
Animal reproduction and development toxicity studies have not been conducted with retifanlimab. A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the foetus. In murine models of pregnancy, blockade of PD-L1 signaling has been shown to disrupt tolerance to the foetus and to result in an increase in foetal loss; therefore, potential risks of administering retifanlimab during pregnancy include increased rates of abortion or stillbirth. As reported in the literature, there were no malformations related to the blockade of PD-1/PD-L1 signaling in the offspring of these animals; however, immune-mediated disorders occurred in PD-1 and PD-L1 knockout mice. Based on its mechanism of action, foetal exposure to retifanlimab may increase the risk of developing immune-mediated disorders or altering the normal immune response.
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