Imfinzi, 50 mg/ml 10 ml

Pharmacodynamics

Mechanism of Action

The expression of programmed cell death receptor 1 (PD-L1) ligand protein is a response to the effects of the adaptive immune system that allows tumors to avoid detection and elimination by the immune system.

PD-L1 expression can be induced by inflammatory signals (e.g. IFN-gamma) and occurs in both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1).

Binding to the corresponding receptors, PD-L1 reduces cytotoxic activity of T cells, proliferation and cytokine production.

Durvalumab is a fully human, high-affinity monoclonal antibody, immunoglobulin G1 kappa (IgGlK) that selectively blocks PD-L1 interaction with PD-1 or CD80 (B7.1), while not affecting PD-1 and PD-L2 interaction.

Durvalumab does not induce antibody-dependent cellular cytotoxicity. Selective blockade of interactions between PD-L1 and PD-1 and PD-L1 and CD80 leads to an increased antitumor immune response, which can lead to tumor elimination.

In preclinical studies, PD-L1 blockade resulted in increased T-lymphocyte activation and reduced tumor size.

Pharmacokinetics

The pharmacokinetics of durvalumab were studied in 1902 patients, with doses ranging from 0.1 mg/kg to 20 mg/kg and the drug administered once every two, three or four weeks.

The pharmacokinetic effects increased more than proportionally to the dose (nonlinear pharmacokinetics) at doses of < 3 mg/kg and proportionally to the dose (linear pharmacokinetics) at doses of ≥3 mg/kg. An equilibrium state was reached after approximately 16 weeks.

Based on a population pharmacokinetic analysis that included data from 1878 patients who received the drug at doses ≥10 mg/kg every 2 weeks, the geometric mean volume of distribution at equilibrium (Vss) was 5.64 liters.

The clearance of durvalumab decreased over time, resulting in a geometric mean equilibrium clearance (CLss) of 8.16 mL/hour at day 365 of therapy; the decrease in CLss is not considered clinically significant. Based on baseline clearance, the half-life was approximately 18 days.

Pharmacokinetics in Special Patient Groups

Age (19-96 years), body weight (34-149 kg), sex, presence of antibodies to durvalumab, albumin concentration, lactate dehydrogenase activity, creatinine concentration, soluble PD-L1 concentration, tumor type, race, Mild renal impairment (creatinine clearance (CK) 60-89 mL/min), moderate renal impairment (CK 30-59 mL/min), mild renal impairment (bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (ACT) activity > HGH or bilirubin concentration > HGH up to 1.5×HGH for any ACT activity) and general status according to the WHO/ECOG scale had no clinically significant effect on the pharmacokinetics of durvalumab.

The effect of severe renal impairment (CKR 15-29 mL/min) or moderate hepatic impairment (bilirubin concentration >1.5×VGN to 3×VGN and any ACT activity) and severe hepatic impairment (bilirubin concentration >3×VGN and any ACT activity) on durvalumab pharmacokinetics is unknown.

Elderly Patients

Dose adjustment in elderly patients (≥65 years) is not required. Of the 476 patients with locally advanced unresectable non-small cell lung cancer (NSCLC) in the PACIFIC (primary efficacy evaluation population) study who received Imfinsi®, 215 patients were 65 years of age or older. Overall, there were no differences in safety profiles between patients aged 65 and older and younger patients.

Indications

Active ingredient

Composition

How to take, the dosage

Interaction

Contraindications

With caution: severe autoimmune diseases in the active stage, in which further activation of the immune system may be potentially life threatening.

Overdose

Pregnancy use