Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor 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. Cemiplimab potentiates T cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD-L1 and PD-L2 ligands.
Concentration data were collected in 548 patients with various solid tumours, including 178 patients with CSCC, who received cemiplimab. At dosing regimens of 1 mg/kg to 10 mg/kg every 2 weeks and 350 mg every 3 weeks, kinetics of cemiplimab were observed to be linear and dose proportional, suggesting saturation of the target-mediated pathway over the dosing interval. Similar exposures to cemiplimab are achieved with the doses of 350 mg every 3 weeks and 3 mg/kg every 2 weeks. With 350 mg every 3 weeks, the mean steady-state concentration of cemiplimab ranged between Cmax of 168 mg/l and a C trough of 61 mg/l. Steady-state exposure is achieved after approximately 4 months of treatment.
Cemiplimab is administered via the intravenous route and hence is completely bioavailable.
Distribution
Cemiplimab is primarily distributed in the vascular system with a volume of distribution at steady-state (Vss) is 5.2 l.
Specific metabolism studies were not conducted because cemiplimab is a protein. Cemiplimab is expected to degrade to small peptides and individual amino acids.
Clearance of cemiplimab is linear at doses of 1 mg/kg to 10 mg/kg every two weeks. Cemiplimab clearance after the first dose is approximately 0.33 l/day. The total clearance appears to decrease by approximately 35% over time, resulting in a steady state clearance (CLss) of 0.21 l/day; the decrease in CL is not considered clinically relevant. The within dosing interval half-life at steady state is 19.4 days.
At the dosing regimens of 1 mg/kg to 10 mg/kg every two weeks, kinetics of cemiplimab were observed to be linear and dose proportional, suggesting saturation of the target-mediated pathway.
Special populations
A population PK analysis suggests that the following factors have no clinically significant effect on the exposure of cemiplimab: age, gender, body weight, race, cancer type, albumin level, mild hepatic impairment and renal impairment.
Renal impairment
The effect of renal impairment on the exposure of cemiplimab was evaluated by a population PK analysis in patients with mild (CLcr 60 to <89 ml/min; n=197), moderate (CLcr 30 to <60 ml/min; n=90), or severe (CLcr <30 ml/min; n=4) renal impairment. No clinically important differences in the exposure of cemiplimab were found between patients with renal impairment and patients with normal renal function. Cemiplimab has not been studied in patients with CLcr <25 ml/min.
The effect of hepatic impairment on the exposure of cemiplimab was evaluated by population PK analysis. In patients with mild hepatic impairment (n=5) (total bilirubin [TB] greater than 1.0 to 1.5 times the upper limit of normal [ULN] and any aspartate aminotransferase [AST]); no clinically important differences in the exposure of cemiplimab were found compared to patients with normal hepatic function. Cemiplimab has not been studied in patients with moderate or severe hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations.
No studies have been performed to test the potential of cemiplimab for carcinogenicity or genotoxicity. Animal reproduction studies have not been conducted with cemiplimab. As reported in the literature, PD-1/PD-L1 signalling pathway plays a role in sustaining pregnancy by maintaining immunological tolerance and studies have shown that PD-1 receptor blockade results in early termination of pregnancy. The increase of spontaneous abortion and/or resorption in animals with restricted PD-L1 expression (knock-out or anti-PD1/PD-L1 monoclonal antibodies) has been shown in both mice and monkeys. These animal species have similar maternal-foetal interface to that in humans.
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