Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the programmed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 on cytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses. Avelumab has also shown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC).
Avelumab pharmacokinetics (PK) was assessed using a population PK approach for avelumab as monotherapy and avelumab in combination with axitinib.
Based on a population PK analysis for avelumab as monotherapy and in combination with axitinib, there are no expected clinically meaningful differences in exposure of avelumab between settings administered every 2 weeks at 800 mg or 10 mg/kg.
Avelumab is expected to be distributed in the systemic circulation and to a lesser extent in the extracellular space. The volume of distribution at steady state was 4.72 L.
Consistent with a limited extravascular distribution, the volume of distribution of avelumab at steady state is small. As expected for an antibody, avelumab does not bind to plasma proteins in a specific manner.
Based on a population pharmacokinetic analysis from 1 629 patients, the value of total systemic clearance (CL) is 0.59 L/day. In the supplemental analysis, avelumab CL was found to decrease over time: the largest mean maximal reduction (% coefficient of variation [CV%]) from baseline value with different tumour types was approximately 32.1% (CV 36.2%).
Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing at 10 mg/kg every 2 weeks, and systemic accumulation was approximately 1.25-fold.
The elimination half-life (t½) at the recommended dose is 6.1 days based on the population PK analysis.
The exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kg every 2 weeks.
When avelumab 10 mg/kg was administered in combination with axitinib 5 mg, the respective exposures of avelumab and axitinib were unchanged compared to the single agents. There was no evidence to suggest a clinically relevant change of avelumab clearance over time in patients with advanced RCC.
A population pharmacokinetic analysis suggested no difference in the total systemic clearance of avelumab based on age, gender, race, PD-L1 status, tumour burden, renal impairment and mild or moderate hepatic impairment.
Total systemic clearance increases with body weight. Steady-state exposure was approximately uniform over a wide range of body weights (30 to 204 kg) for body weight normalised dosing.
No clinically important differences in the clearance of avelumab were found between patients with mild (glomerular filtration rate (GFR) 60 to 89 mL/min, Cockcroft-Gault Creatinine Clearance (CrCL); n=623), moderate (GFR 30 to 59 mL/min, n=320) and patients with normal (GFR ≥90 mL/min, n=671) renal function.
Avelumab has not been studied in patients with severe renal impairment (GFR 15 to 29 mL/min).
No clinically important differences in the clearance of avelumab were found between patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin between 1 and 1.5 times ULN, n=217) and normal hepatic function (bilirubin and AST ≤ ULN, n=1 388) in a population PK analysis. Hepatic impairment was defined by National Cancer Institute (NCI) criteria of hepatic dysfunction.
Avelumab has not been studied in patients with moderate hepatic impairment (bilirubin between 1.5 and 3 times ULN) or severe hepatic impairment (bilirubin >3 times ULN).
The pharmacokinetics of avelumab was evaluated in 21 children and adolescents from 3 years to 17 years in study MS100070-0306 receiving either 10 mg/kg (N=6) or 20 mg/kg (N=15) avelumab intravenously every 2 weeks until confirmed progression, death, or unacceptable toxicity.
The paediatric PK parameters and the corresponding PK profiles for all patients were evaluated according to dosing and stratified by bodyweight.
The exposure in paediatric patients receiving 20 mg/kg avelumab were similar or higher compared to those in adults receiving 10 mg/kg or 800 mg avelumab. In paediatric patients receiving 10 mg/kg avelumab the exposure was lower compared to those in adults.
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing period. Perivascular mononuclear cell cuffing was observed in the brain and spinal cord of monkeys treated with avelumab at ≥20 mg/kg for 3 months. Although there was no clear dose-response relationship, it cannot be excluded that this finding was related to avelumab treatment.
Animal reproduction studies have not been conducted with avelumab. The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss. These results indicate a potential risk that administration of avelumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
No studies have been conducted to assess the potential of avelumab for carcinogenicity or genotoxicity.
Fertility studies have not been conducted with avelumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the female reproductive organs. Many of the male monkeys used in these studies were sexually immature and thus no explicit conclusions regarding effects on male reproductive organs can be made.
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