Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
The steady state AUC, Ctrough, and Cmax in patients administered with 1,500 mg every 4 weeks are 
6% higher, 19% lower, and 55% higher than those administered with 10 mg/kg every 2 weeks,  respectively. Based on the modeling of pharmacokinetic data and exposure relationships for safety,  there are no anticipated clinically meaningful differences in efficacy and safety for the doses of 1,500  mg every 4 weeks compared to 10 mg/kg every 2 weeks in patients weighing > 30 kg with NSCLC.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetics of durvalumab as a single agent was studied in patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three or four weeks.


PK exposure increased more than dose-proportionally at doses less than 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks.
The pharmacokinetics of durvalumab is similar when assessed as a single agent, when in combination with chemotherapy and when in combination with tremelimumab and when in combination with tremelimumab and platinum-based chemotherapy.



Distribution
The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution (Vss) was 5.4 (13.1%) L.


Elimination
Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 21 (26%) days.


Specific Populations
There were no clinically significant differences in pharmacokinetics of durvalumab  based on age (18-96 years), body weight (31-175 kg), sex, race (White, Black, 
Asian, Native Hawaiian, Pacific Islander, or Native American), albumin levels (4-57 g/L), lactate dehydrogenase levels (18-15,800 U/L), soluble PD-L1 (67-3,470  pg/mL), tumor type (NSCLC, SCLC, BTC and HCC), varying degrees of organ  impairment including mild to moderate renal impairment (CLcr 30 to 89 mL/min),  mild to moderate hepatic impairment (bilirubin ≤ 3*ULN and any AST).

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


12.4 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 comparison of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies including those of IMFINZI.


Of the 2,280 patients who received IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as a single-agent, 69 patients (3%) tested positive for ADAs and 12 (0.5%) tested positive for neutralizing antibodies. The development of ADAs against durvalumab appears to have no clinically relevant effect on its pharmacokinetics or safety.


Of the 201 patients in the CASPIAN study who received IMFINZI 1,500 mg every 3 weeks in combination with chemotherapy for four doses followed by IMFINZI 1,500 mg every 4 weeks, no patients tested positive for ADAs.


Of the 240 patients in the TOPAZ-1 study who received IMFINZI 1,500 mg every 3 weeks in combination with chemotherapy up to 8 cycles followed by IMFINZI 1,500 mg every 4 weeks, 2 (0.8%) patients tested positive for treatment-emergent ADAs and neutralizing antibodies,
respectively. There were insufficient numbers of patients with ADAs or neutralizing antibodies (2 patients each) to determine whether ADAs have an impact on pharmacokinetics, pharmacodynamics, safety and/or effectiveness of IMFINZI.


During the 12 week treatment period in the HIMALAYA study, of the 294 patients who  received IMFINZI once every 4 weeks in combination with a single dose of tremelimumab  and who were evaluated for the presence of ADAs against IMFINZI at predose week 0, week 
4 and week 12, 3.1% (9/294) of patients tested positive for anti-durvalumab-antibodies.

Among the 9 patients who tested positive for ADA, 55.6% (5/9) tested positive for neutralizing  antibodies against durvalumab. There was no identified clinically significant effect of anti-  durvalumab antibodies on the safety of durvalumab; however, the effect of ADAs on the  pharmacokinetics and effectiveness of durvalumab is unknown.

During 16 weeks of treatment during the POSEIDON study, among 286 patients who received IMFINZI 1,500 mg in combination with tremelimumab 75 mg every 3 weeks for five doses and chemotherapy for four cycles followed by IMFINZI 1,500 mg every 4 weeks 10% (29/286) of patients tested positive for anti- durvalumab antibodies with predose sampling at week 0, week 3 and week 12. Among the 29 patients who tested positive for ADAs, 10% (3/29) tested positive for neutralizing antibodies against durvalumab. The geometric mean of durvalumab concentration in patients with ADA positive was 46 mcg/mL compared to 89 mcg/mL in patients with ADA negative. There was no clinically significant effect of anti-durvalumab antibodies on the safety of durvalumab; however, there is insufficient data to assess whether the observed 
ADA associated pharmacokinetic changes reduce effectiveness of durvalumab.