Imfinzi, 50 mg/ml 2.4ml

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 receiving the drug at doses ≥10 mg/kg every 2 weeks, the geometric mean volume of distribution in the equilibrium state (Vss) was 5.64 L.

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

Nonresectable locally disseminated non-small cell lung cancer in adult patients with no disease progression after platinum-based chemoradiotherapy.

Active ingredient

Durvalumab

Composition

1 ml of concentrate contains:

Active ingredient:

• durvalumab 50 mg

Excipients:

• L-histidine 2 mg,
• L-histidine hydrochloride monohydrate 2.7 mg,
• α,α-trehalose dihydrate 104 mg,
• polysorbate 80 0,2 mg,
• water for injection approximately 900 mg.

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How to take, the dosage

The recommended dose of the drug Imfinsi® is 10 mg/kg in the form of an intravenous infusion lasting at least 60 minutes. The drug should be administered once every 2 weeks until disease progression or development of unacceptable toxicity.

Increasing or decreasing the drug dose is not recommended. Taking into account the tolerability and safety of the drug it may be necessary to suspend therapy or cancel it.

Interaction

The use of systemic glucocorticosteroids or immunosuppressants prior to durvalumab therapy, with the exception of systemic glucocorticosteroids at a physiological dose (up to 10 mg prednisolone daily or equivalent), is not recommended because of the possible effect on the pharmacodynamic activity and effectiveness of durvalumab.

Nevertheless, systemic glucocorticosteroids and immunosuppressants may be used after durvalumab therapy to treat immune-mediated adverse reactions (see section “Special Indications”).

Formal studies of drug interactions of durvalumab have not been conducted. Since the main pathways of durvalumab metabolism are protein catabolism involving the reticuloendothelial system and target-mediated clearance, no metabolic interactions with other drugs are expected.

Contraindications

• High sensitivity to durvalumab or excipients of the drug.
• Children under 18 years of age.
• Pregnancy and breast-feeding.
• Moderate to severe liver function impairment.

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

Overdose

There is no specific treatment in case of overdose of Imfinsi® , no overdose symptoms have been established. In case of overdose symptomatic treatment and general supportive measures should be carried out.

Pregnancy use

Women with preserved fertility

Women with preserved fertility should use reliable contraception during therapy with durvalumab and for at least 3 months after the last dose of the drug.
Pregnancy

There are no data on the use of durvalumab in pregnant women. Given the mechanism of action, durvalumab may affect pregnancy and have harmful effects on the fetus when used during pregnancy.

In an allogeneic pregnancy model in mice, it has been shown that disruption of PD-L1 signaling leads to an increased incidence of fetal loss. No reproductive toxicity was detected in animal studies.

Human immunoglobulin IgGl penetrates the placental barrier. In animal studies, durvalumab has also been shown to cross the placental barrier. The use of durvalumab during pregnancy can cause harm to the fetus.

Therefore, durvalumab should not be used during pregnancy and in the absence of reliable contraception during therapy, and for at least 3 months after the last dose of the drug.

Breastfeeding

No information regarding durvalumab excretion into breast milk. Toxicological studies showed low concentrations of durvalumab in the milk of Javanese macaques at 28 days postpartum.

In humans, monoclonal antibodies can be excreted into breast milk, but there are no data on their possible absorption and harm to the newborn. Nevertheless, the risk to breastfed infants cannot be ruled out.

Therefore, either discontinue breastfeeding or refrain from durvalumab therapy, taking into account the benefits of breastfeeding for the infant and the benefits of durvalumab therapy for the woman.

Fertility

There are no data on the possible effects of durvalumab on fertility in animals and humans.