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 tremelimumab have not been fully characterized.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetics of tremelimumab was studied in patients with other solid tumors following administration of doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) administered once every 4 weeks for 4 doses. The pharmacokinetics of tremelimumab as a single dose of 300 mg were evaluated in patients with HCC.

The AUC of tremelimumab increased proportionally from 1 mg/kg to 10 mg/kg every 4 weeks (1 to 10-times the approved recommended dosage) and steady state was achieved at approximately 12 weeks.


Distribution
The geometric mean (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.

Elimination
The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady state. The geometric mean (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady state.

Specific Populations
There were no clinically significant differences in the pharmacokinetics of tremelimumab based on body weight (34 to149 kg), age (18 to 87 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3 to 396 g/L), lactate  dehydrogenase levels (12 to 5570 U/L), soluble PD-L1 (67 to 349 pg/mL), tumor type (NSCLC, HCC), organ dysfunction including mild to moderate renal impairment (CLcr 30 to 89 mL/min),  and mild to moderate hepatic impairment (bilirubin < 3 x ULN and any AST).

The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin >3 x ULN and any AST) on the pharmacokinetics of tremelimumab is unknown.


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 studies, including those of tremelimumab.

In the HIMALAYA study, of the 182 patients who were treated with a single dose of  tremelimumab in combination with durvalumab once in every 4 weeks therapy and evaluable for the presence of ADAs against tremelimumab at predose week 0 and week 4, 11% (20/182)  of patients tested positive for anti-tremelimumab antibodies. Among the 20 patients who tested positive for ADAs 40% (8/20) tested positive for neutralizing antibodies against tremelimumab.

There was no identified clinically significant effect of anti-tremelimumab antibodies on the pharmacokinetics or safety of tremelimumab; however, the effect of ADAs and neutralizing antibodies on the effectiveness of tremelimumab is unknown.
In the POSEIDON study, of the 278 ADA-evaluable patients who were treated with IMJUDO 75  mg for up to five doses in combination with durvalumab 1,500 mg and platinum-based chemotherapy every 3 weeks and evaluated for presence of ADAs against tremelimumab at  pre-dose week 0, week 3, and week 12, 14% (38/278) of patients tested positive for anti- tremelimumab antibodies. Among the 38 patients who tested positive for ADAs, 82% (31/38)  tested positive for neutralizing antibodies against tremelimumab. There was no identified clinically significant effect of anti-tremelimumab antibodies on pharmacokinetics or safety of tremelimumab, however, the effect of ADAs on effectiveness of tremelimumab is unknown.