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 greater than or equal to 3 mg/kg. Steady state was achieved at approximately 16 weeks.
Distribution
The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution was 5.6 (17%) L.
Elimination
Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 22.9% (46.3%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.24 mL/h (37.3%); the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life was approximately 17 (23.2%) days.
Specific Populations
Age (19–96 years), body weight (34-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin less than or equal to ULN and AST greater than ULN or bilirubin greater than 1.0 to 1.5 times ULN and any AST), or ECOG performance status had no clinically significant effect on the pharmacokinetics of durvalumab.
The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin greater than 1.5 to 3.0 times ULN and any AST) or severe hepatic impairment (bilirubin greater than 3.0 times ULN and any AST) on the pharmacokinetics of durvalumab is unknown.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
The carcinogenic and genotoxic potential of durvalumab have not been eva luated.
Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.
13.2 Animal Toxicology and/or Pharmacology
In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus.
14 CLINICAL STUDIES
14.1 Urothelial Carcinoma
The efficacy of IMFINZI was eva luated in Study 1, the urothelial cancer cohort of a multicenter, multi-cohort, open-label clinical trial. In Study 1, 182 patients with locally advanced or metastatic urothelial carcinoma were enrolled. Patients had progressed while on or after a platinum-based therapy, including those who progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant setting. These patients had initiated durvalumab therapy at least 13 weeks prior to the data cut-off date. The trial excluded patients with a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg/day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection. All patients received IMFINZI 10 mg/kg via intravenous infusion eve |
