e metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.
Elimination
After a single intravenous dose of 10 mcg/kg [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine with palonosetron representing approximately 40% of the administered dose. In healthy subjects, the total body clearance of palonosetron was 0.160 ± 0.035 L/h/kg and renal clearance was 0.067± 0.018 L/h/kg. Mean terminal elimination half‑life is approximately 40 hours.
Specific Populations
Pediatric Patients
Single-dose I.V. ALOXI pharmacokinetic data was obtained from a subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg. When the dose was increased from 10 mcg/kg to 20 mcg/kg a dose-proportional increase in mean AUC was observed. Following single dose intravenous infusion of ALOXI 20 mcg/kg, peak plasma concentrations (CT) reported at the end of the 15 minute infusion were highly variable in all age groups and tended to be lower in patients < 6 years than in older patients. Median half-life was 29.5 hours in overall age groups andranged from about 20 to 30 hours across age groups after administration of 20 mcg/kg.
The total body clearance (L/h/kg) in patients 12 to 17 years old was similar to that in healthy adults. There are no apparent differences in volume of distribution when expressed as L/kg.
Table 3: Pharmacokinetics Parameters in Pediatric Cancer Patients Following Intravenous Infusion of ALOXI at 20 mcg/kg over 15 min PK Parametera Pediatric Age Group
<2 y 2 to <6 y 6 to <12 y 12 to <17 y
N=12 N=42 N=38 N=44
CTb, ng/L 9025 (197) 9414 (252) 16275 (203) 11831 (176)
N=5 N=7 N=10
AUC 0-∞ , h·mcg/L 103.5 (40.4) 98.7 (47.7) 124.5 (19.1)
N=6 N=14 N=13 N=19
Clearancec , L/h/kg 0.31 (34.7) 0.23 (51.3) 0.19 (46.8) 0.16 (27.8)
Vssc, L/kg 6.08 (36.5) 5.29 (57.8) 6.26 (40.0) 6.20 (29.0)
a Geometric Mean (CV) except for t1/2 which is median values.
b CT is the plasma palonosetron concentration at the end of the 15 minute infusion.
c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityIn a 104-week carcinogenicity study in CD-1 mice, animals were treated with oral doses of palonosetron at 10, 30, and 60 mg/kg/day. Treatment with palonosetron was not tumorigenic. The highest tested dose produced a systemic exposure to palonosetron (Plasma AUC) of about 150 to 289 times the human exposure (AUC= 29.8 h·mcg/L) at the recommended intravenous dose of 0.25 mg. In a 104-week carcinogenicity study in Sprague-Dawley rats, male and female rats were treated with oral doses of 15, 30, and 60 mg/kg/day and 15, 45, and 90 mg/kg/day, respectively. The highest doses produced a systemic exposure to palonosetron (Plasma AUC) of 137 and 308 times the human exposure at the recommended dose. Treatment with palonosetron produced increased incidences of adrenal benign pheochromocytoma and combined benign and malignant pheochromocytoma, increased incidences of pancreatic Islet cell adenom |
