Programmed death-ligand 1 (PD-L1) may be expressed on tumour cells and/or tumour-infiltrating immune cells, and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.
Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to PD-L1 and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity. Atezolizumab spares the PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.
Exposure to atezolizumab increased dose proportionally over the dose range 1 mg/kg to 20 mg/kg including the fixed dose 1,200 mg administered every 3 weeks. A population analysis that included 472 patients described atezolizumab pharmacokinetics for the dose range: 1 to 20 mg/kg with a linear two-compartment disposition model with first-order elimination. A population pharmacokinetic analysis suggests that steady-state is obtained after 6 to 9 weeks (2 to 3 cycles) of repeated dosing. The systemic accumulation in area under the curve, maximum concentration and trough concentration was 1.91, 1.46 and 2.75-fold, respectively.
Atezolizumab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
A population pharmacokinetic analysis indicates that central compartment volume of distribution is 3.28 L and volume at steady-state is 6.91 L in the typical patient.
The metabolism of atezolizumab has not been directly studied. Antibodies are cleared principally by catabolism.
A population pharmacokinetic analysis indicates that the clearance of atezolizumab is 0.200 L/day and the typical terminal elimination half-life is 27 days.
Based on population PK and exposure-response analyses age (21-89 years), region, ethnicity, renal impairment, mild hepatic impairment, level of PD-L1 expression, or ECOG performance status have no effect on atezolizumab pharmacokinetics. Body weight, gender, positive ADA status, albumin levels and tumour burden have a statistically significant, but not clinically relevant effect on atezolizumab pharmacokinetics. No dose adjustments are recommended.
No dedicated studies of atezolizumab have been conducted in elderly patients. The effect of age on the pharmacokinetics of atezolizumab was assessed in a population pharmacokinetic analysis. Age was not identified as a significant covariate influencing atezolizumab pharmacokinetics based on patients of age range of 21-89 years (n=472), and median of 62 years of age. No clinically important difference was observed in the pharmacokinetics of atezolizumab among patients <65 years (n=274), patients between 65−75 years (n=152) and patients >75 years (n=46).
No studies have been conducted to investigate the pharmacokinetics of atezolizumab in children or adolescents.
No dedicated studies of atezolizumab have been conducted in patients with renal impairment. In the population pharmacokinetic analysis, no clinically important differences in the clearance of atezolizumab were found in patients with mild (estimated glomerular filtration rate [eGFR] 60 to 89 mL/min/1.73 m²; n=208) or, moderate (eGFR 30 to 59 mL/min/1.73 m²; n=116) renal impairment compared to patients with normal (eGFR greater than or equal to 90 mL/min/1.73 m²; n=140) renal function. Only a few patients had severe renal impairment (eGFR 15 to 29 mL/min/1.73 m²; n=8). The effect of severe renal impairment on the pharmacokinetics of atezolizumab is unknown.
No dedicated studies of atezolizumab have been conducted in patients with hepatic impairment. In the population pharmacokinetic analysis, there were no clinically important differences in the clearance of atezolizumab between patients with mild hepatic impairment (bilirubin ≤ULN and AST >ULN or bilirubin >1.0 × to 1.5 × ULN and any AST, n=71) and normal hepatic function (bilirubin and AST ≤ULN, n=401). No data are available in patients with either moderate or severe hepatic impairment. Hepatic impairment was defined by the National Cancer Institute (NCI) criteria of hepatic dysfunction. The effect of moderate or severe hepatic impairment (bilirubin >1.5 × to 3 × ULN and any AST or bilirubin >3 × ULN and any AST) on the pharmacokinetics of atezolizumab is unknown.
Carcinogenicity studies have not been performed to establish the carcinogenic potential of atezolizumab.
Mutagenicity studies have not been performed to establish the mutagenic potential of atezolizumab. However, monoclonal antibodies are not expected to alter DNA or chromosomes.
No fertility studies have been conducted with atezolizumab; however assessment of the cynomolgus monkey male and female reproductive organs was included in the chronic toxicity study. Weekly administration of atezolizumab to female monkeys at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose caused an irregular menstrual cycle pattern and a lack of newly formed corpora lutea in the ovaries which were reversible. There was no effect on the male reproductive organs.
No reproductive or teratogenicity studies in animals have been conducted with atezolizumab. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to immune-related rejection of the developing foetus resulting in foetal death. Administration of atezolizumab could cause foetal harm, including embryo-foetal lethality.