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palonosetron HCl injection Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Palonosetron is a 5-HT3 receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors.

Cancer chemotherapy may be associated with a high incidence of nausea and vomiting, particularly when certain agents, such as cisplatin, are used. 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is thought that chemotherapeutic agents produce nausea and vomiting by releasing serotonin from the enterochromaffin cells of the small intestine and that the released serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.

Postoperative nausea and vomiting is influenced by multiple patient, surgical and anesthesia related factors and is triggered by release of 5-HT in a cascade of neuronal events involving both the central nervous system and the gastrointestinal tract. The 5-HT3 receptor has been demonstrated to selectively participate in the emetic response.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of intravenous palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to intravenous ondansetron and dolasetron in CINV clinical trials. In PONV clinical trials the effect of palonosetron on the QTc interval was no different from placebo. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarization and to prolong action potential duration.

At a dose of 9 times the maximum recommended adult dose, Palonosetron HCl Injection does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

After intravenous dosing of palonosetron HCl in healthy subjects and cancer patients, an initial decline in palonosetron plasma concentrations is followed by a slow elimination from the body. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0–∞) are generally dose-proportional over the dose range of 0.3 to 90 mcg/kg in healthy subjects and in cancer patients. Following a single intravenous dose of palonosetron HCl at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer patients, mean (±SD) maximum plasma concentration was estimated to be 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9 h∙mcg/L.

Following intravenous administration of Palonosetron HCl Injection 0.25 mg once every other day for 3 doses in 11 cancer patients, the mean increase in plasma palonosetron concentration from Day 1 to Day 5 was 42±34%. Following intravenous administration of palonosetron injection 0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD) increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%.

After intravenous dosing of Palonosetron HCl Injection in patients undergoing surgery (abdominal surgery or vaginal hysterectomy), the pharmacokinetic characteristics of palonosetron were similar to those observed in cancer patients.

Distribution

Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.

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.

Metabolism

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron. These metabolites each have less than 1% of the 5-HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have suggested that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolizers of CYP2D6 substrates.

Specific Populations

Pediatric Patients

Pharmacokinetic data was obtained from a subset of pediatric cancer patients that received 10 mcg/kg or 20 mcg/kg as a single intravenous dose of Palonosetron HCl Injection. When the dose was increased from 10 mcg/kg to 20 mcg/kg a dose-proportional increase in mean AUC was observed. Peak plasma concentrations (CT) reported at the end of the 15-minute infusion of 20 mcg/kg were highly variable in all age groups and tended to be lower in patients less than 6 years than in older patients as shown in Table 4. The median half-life was 30 hours in overall age groups and ranged 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 4: Pharmacokinetics Parameters in Pediatric Cancer Patients following Intravenous Infusion of 20 mcg/kg Palonosetron HCl Injection Over 15 minutes
PK Parameter *Pediatric Age Group
Less than 2 years2 years to less than 6 years6 years to less than 12 years12 years to less than 17 years
*
Geometric Mean (CV) except for t1/2 which is median values
CT is the plasma palonosetron concentration at the end of the 15-minute infusion
Clearance and Vss calculated from 10 and 20 mcg/kg and are weight adjusted
N=12N=42N=38N=44
CT , ng/L9025 (197)9414 (252)16275 (203)11831 (176)
N=5N=7N=10
AUC0–∞, h∙mcg/L103.5 (40.4)98.7 (47.7)124.5 (19.1)
N=6N=14N=13N=19
Clearance , L/h/kg0.31 (34.7)0.23 (51.3)0.19 (46.8)0.16 (27.8)
Vss , L/kg 6.08 (36.5)5.29 (57.8)6.26 (40.0)6.20 (29.0)

Racial or Ethnic Groups

The pharmacokinetics of palonosetron were characterized in 24 healthy Japanese subjects over an intravenous dose range of 3 to 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, this increase is not considered to be clinically meaningful.

Patients with Renal Impairment

Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in patients with severe renal impairment relative to healthy subjects. This increase is not considered clinically meaningful.

Patients with Hepatic Impairment

Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects.

Drug Interaction Studies

In vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Dexamethasone

Coadministration of 0.25 mg Palonosetron HCl Injection and 20 mg dexamethasone administered intravenously in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

Oral Aprepitant

In an interaction study in healthy subjects where a single 0.25 mg intravenous dose of Palonosetron HCl Injection was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase).

Metoclopramide

A study in healthy subjects involving a single 0.75 mg intravenous dose of Palonosetron HCl Injection and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

Corticosteroids, Analgesics, Antiemetics/Antinauseants, Antispasmodics and Anticholinergic Agents

In controlled clinical trials, Palonosetron HCl Injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

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