Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of atezolizumab have not been fully characterized.

Pharmacokinetic Properties

12.3   Pharmacokinetics
Atezolizumab exposure increased dose proportionally over the dose range of 1 mg/kg to 20 mg/kg (0.07 to 1.33 times of the approved recommended doses), including a dose of 1200 mg administered every 3 weeks. Steady state was achieved after 6 to 9 weeks following multiple doses. The systemic accumulation ratio for every 2 weeks administration and every 3 weeks administration was 3.3- and 1.9- fold, respectively.
Distribution
The volume of distribution at steady state is 6.9 L.
Elimination
The clearance (CV%) is 0.2 L/day (29%) and the terminal half-life is 27 days. Atezolizumab clearance was found to decrease over time, with a mean maximal reduction (CV%) from baseline value of 17% (41%); however, the decrease in clearance was not considered clinically relevant.
Specific Populations
The following factors had no clinically significant effect on the systemic exposure of atezolizumab: age (2 to 89 years), body weight, sex, albumin levels, tumor burden, region or race, mild or moderate renal impairment [estimated glomerular filtration rate (eGFR) 30 to 89 mL/min/1.73 m2], mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5 × ULN and any AST), moderate hepatic impairment (bilirubin >1.5 to 3x ULN and any AST), level of PD-L1 expression, or performance status.
Pediatric Patients
Atezolizumab serum concentrations with weight-based dosing at 15 mg/kg up to a maximum of 1200 mg every 3 weeks, in pediatric patients (2 years to <17 years) with relapsed or progressive solid tumors and lymphomas, are comparable to those of adult patients receiving 1200 mg every 3 weeks; while the exposure tended to be lower in pediatric patients less than 12 years old, this is not considered to be clinically relevant.
12.6 Immunogenicity
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other products.
During the first year of treatment with TECENTRIQ across 8 clinical studies, 13% to 36% of patients developed anti-atezolizumab antibodies. Median atezolizumab clearance in patients who tested positive for ADA was 19% (minimum 18%, maximum 49%) higher as compared to atezolizumab clearance in patients who tested negative for ADA; this change in clearance is not expected to be clinically significant.
In OAK and IMbrave150, exploratory analyses showed that the subset of patients who were ADA-positive appeared to have less efficacy (effect on overall survival) as compared to patients who tested negative for ADA [see Clinical Studies (14.1, 14.3)]. In study IMpower150, the impact of ADA on efficacy did not appear to be clinically significant [see Clinical Studies (14.1)]. In the remaining studies, there is insufficient information to characterize the effect of ADA on efficacy.
The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions.
Across clinical studies, 4.3% to 27.5% of neutralizing antibody (NAb)-evaluable patients had a positive NAb status at any timepoint post-treatment. The effect of NAb on atezolizumab exposure and safety did not appear to be clinically significant. The effect of NAb on key efficacy endpoints is uncertain due to small sample sizes.