ly in plasma, erythrocytes and many of the major organs (i.e., intestine, kidney, liver and lung). Angiotensin II type 1 receptor (AT1) mediated activity of angiotensin III is approximately 40% of angiotensin II; however, aldosterone synthesis activity is similar to angiotensin II. Angiotensin-(1-7) exerts the opposite effects of angiotensin II on AT1 receptors and causes vasodilation.
Specific Populations
No formal pharmacokinetic studies were conducted with GIAPREZA in the following specific populations.
Renal Impairment
The clearance of angiotensin II is not dependent on renal function. Therefore, the pharmacokinetics of GIAPREZA are not expected to be influenced by renal impairment.
Hepatic Impairment
The clearance of angiotensin II is not dependent on hepatic function. Therefore, the pharmacokinetics of GIAPREZA are not expected to be influenced by hepatic impairment.
Age
The effect of age was analyzed in the 163 patients receiving GIAPREZA in ATHOS-3. There were no significant differences in pharmacokinetics between age groups (< 65 years / ≥ 65 years).
Male and Female Patients
The effect of sex was analyzed in the 163 patients receiving GIAPREZA in ATHOS-3. There were no significant differences in pharmacokinetics between male and female patients.
13. NONCLINICAL TOXICOLOGY
13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
No genetic toxicity studies have been conducted with GIAPREZA. No carcinogenicity or fertility studies with GIAPREZA have been conducted in animals.
13.2. Animal Toxicology and/or Pharmacology
No animal toxicology studies were conducted with GIAPREZA.
13.3. Safety Pharmacology
In a cardiovascular safety pharmacology study in normotensive dogs, GIAPREZA doses of 150, 450, and 1800 ng/kg (5, 15 and 60 ng/kg/min) were infused intravenously for 30 minutes each. At ≥ 450 ng/kg, GIAPREZA caused significantly elevated MAP and systemic vascular resistance, as expected. The 1800 ng/kg dose also caused increased heart rate, increased systemic vascular resistance, increased left ventricular systolic and end-diastolic pressures, and PR interval prolongation. GIAPREZA did not significantly alter respiratory rate or cause electrocardiographic changes in QRS duration or QTc.
14. CLINICAL STUDIES
14.1. ATHOS-3
The Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial was a double-blind study in which 321 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomized 1:1 to GIAPREZA or placebo. Doses of GIAPREZA or placebo were titrated to a target mean arterial pressure (MAP) of ≥ 75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained. From Hour 3 to Hour 48, GIAPREZA or placebo were titrated to maintain MAP between 65 and 70 mmHg while reducing doses of other vasopressors. The primary endpoint was the percentage of subjects who achieved either a MAP ≥ 75 mmHg or a ≥ 10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours.
91% of subjects had septic shock; the remaining subjec
