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 from 1063 patients with various solid tumours who received intravenous cemiplimab were combined in a population PK analysis.
At 350 mg Q3W, the mean cemiplimab concentrations at steady-state ranged between a Ctrough of 59 mg/l and a concentration at end of infusion (Cmax) of 171 mg/l. Steady-state exposure is achieved after approximately 4 months of treatment.
Cemiplimab exposure at steady-state in patients with solid tumours is similar at 350 mg Q3W and at 3 mg/kg Q2W.
Cemiplimab is administered via the intravenous route and hence is completely bioavailable.
Cemiplimab is primarily distributed in the vascular system with a volume of distribution at steady-state (Vss) of 5.9 l. Median Tmax occurs at the end of the 30-minute infusion.
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 0.25 l/day. The total clearance appears to decrease by approximately 11% over time, resulting in a steady-state clearance (CLss) of 0.22 l/day; the decrease in CL is not considered clinically relevant. The within dosing interval half-life at steady-state is 22 days.
At the dosing regimens of 1 mg/kg to 10 mg/kg every two weeks, pharmacokinetics of cemiplimab were linear and dose proportional, suggesting saturation of the systemic target-mediated pathway.
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, renal impairment, and mild to moderate hepatic 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=396), moderate (CLcr 30 to 59 ml/min; n=166), or severe (CLcr 15 to 29 ml/min; n=7) 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 <21 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=22) (total bilirubin [TB] greater than 1.0 to 1.5 times the upper limit of normal [ULN] and any aspartate aminotransferase [AST]) and patients with moderate hepatic impairment (n=3) (total bilirubin >1.5 times ULN up to 3.0 times ULN) and any 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 severe hepatic impairment. There are insufficient data in patients with 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-PD-1/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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