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Aloxi Capsules

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Aloxi Capsules

Aloxi Capsules

CLINICAL PHARMACOLOGY

Mechanism of Action

Palonosetron is a 5-HT3receptor 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. 5­HT3 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.

Pharmacodynamics

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.

The effect of palonosetron on QTc interval was evaluated in a double blind, randomized, parallel, placebo and positive (moxifloxicin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of intravenously administered palonosetron at single doses of 0.25 mg, 0.75 mg or 2.25 mg in 221 healthy subjects. The study demonstrated no significant effect on any ECG interval including QTc duration (cardiac repolarization) at doses up to 2.25 mg.

Clinical trials revealed that oral palonosetron had comparable effects on blood pressure, heart rate, and ECG parameters as intravenous palonosetron.

Pharmacokinetics

Absorption

Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using bufferedm solution mean maximum palonosetron concentrations (Cmax) and area under the concentration-time curve (AUC0-∞) were dose proportional over the dose range of 3.0 to 80 µg/kg in healthy subjects.

In 36 healthy male and female subjects given a single oral dose of ALOXI (palonosetron hcl capsules) Capsules 0.5 mg, maximum plasma palonosetron concentration (C max) was 0.81 ± nd time to maximum concentration (Tmax) was 5.1 ± 35% higher and the mean Cmax was 26% higher than in male subjects (n=18).

In 12 cancer patients given a single oral dose of palonosetron 0.5 mg one hour prior to chemotherapy, Cmax was 0.93 ± 0.34 ng/mL and Tmax was 5.1 ± 5.9 hours. The AUC was 30% higher in cancer patients than in healthy subjects. The mean PK parameters after a single oral dose of 0.5 mg palonosetron are compared between healthy subjects and cancer patients (Table 2).

Table 2: Mean PK parameters1 (± SD) of palonosetron after a single dose of 0.5 mg Aloxi (palonosetron hcl capsules) Capsules in healthy subjects and cancer patients

PK Parameters Healthy subjects
(n=36)
Cancer patients
(n=12)
Cmax (ng/mL) 0.81 ±0.17 0.93 ± 0.34
Tmax (h) 5.1 ±107 5.1± 5.9
AUC(ng·h/mL) 38.2 ±11.7 49.7± 12.2
t1/2 (h) 37 ±12 48± 19
1across-study comparison

A high fat meal did not affect the Cmax and AUC of oral palonosetron. Therefore, ALOXI (palonosetron hcl capsules) Capsules may be taken without regard to meals.

Distribution

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

Metabolism

Palonosetron is eliminated by multiple routes with approximately 50% metabolized to form two primary metabolites: N-oxide-palonosetron and 6-Shydroxy- 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.

Elimination

Following administration of a single oral 0.75 mg dose of [14C]­palonosetron to six healthy subjects, 85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was eliminated in feces. The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. In healthy subjects given ALOXI (palonosetron hcl capsules) Capsules 0.5 mg, the terminal elimination half-life (t½) of palonosetron was 37 (mean ± dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 SD) and renal clearance was 66.5

Special Populations

[see Use In Sprcific Populations]

Clinical Studies

Study 1 was a multicenter, randomized, double-blind active control clinical trial of 635 patients set to receive moderately emetogenic cancer chemotherapy. A single-dose of 0.25 mg, 0.5 mg, or 0.75 mg oral ALOXI (palonosetron hcl capsules) capsules given one hour prior to moderately emetogenic chemotherapy was compared to a single-dose of 0.25 mg I.V. ALOXI (palonosetron hcl capsules) given 30 minutes prior to chemotherapy. Patients were randomized to either dexamethasone or placebo in addition to their assigned treatment. The majority of patients in the study were women (73%), white (69%), and naïve to previous chemotherapy (59%). The primary efficacy endpoint was Complete Response (no emetic episodes and no rescue medication) assessed in the acute phase (0-24 hours). A key secondary efficacy endpoint was Complete Response assessed in the delayed phase (24-120 hours). Other secondary endpoints included Complete Response for the acute plus delayed phases (0-120 hours) and No Nausea for the acute and delayed phases.

Efficacy was based on demonstrating non-inferiority of oral palonosetron doses compared to the approved I.V. formulation. Non-inferiority criteria were met if the lower bound of the two-sided 98.3% confidence interval for the difference in complete response rates of oral palonosetron dose minus approved I.V. formulation was larger than -15%. The non-inferiority margin was 15%.

Efficacy Results

As shown in Table 3, ALOXI (palonosetron hcl capsules) Capsules 0.5 mg demonstrated non-inferiority to the active comparator during the 0 to 24 hour time interval; however, for the 24 to 120 hour time period, non-inferiority was not shown. The additional two oral palonosetron dose levels showed similar results.

Table 3: Proportion of Patients Achieving Complete Response Post-Chemotherapy

Time Period Oral ALOXI 0.5 mg (N=160) I.V. ALOXI 0.25 mg (N=162) Difference [Two-sided 98.3% Confidence Interval]*: Oral ALOXI minus I.V. ALOXI Comparator
0-24 hr 76.3% 70.4% 5.9% [-6.5%, 18.2%]
24-120 hr 62.5% 65.4% -2.9% [-16.3%, 10.5%]
* To adjust for multiplicity of treatment groups, a lower-bound of a two-sided 98.3% confidence interval was used to compare to -15%, the negative value 12 hours in of the non-inferiority margin.

As indicated in the data above, analysis of the key secondary endpoint showed35 mL/h/kg (mean that a single dose of ALOXI (palonosetron hcl capsules) Capsules 0.5 mg was numerically similar to a 18.2 mL/h/kg. single dose of I.V. ALOXI (palonosetron hcl capsules) 0.25 mg, however, statistical non-inferiority was not demonstrated. For ALOXI (palonosetron hcl capsules) Capsules 0.5 mg versus I.V. ALOXI (palonosetron hcl capsules) 0.25 mg, the proportion of patients with complete response at 0-120 hours was 58.8% versus 59.3%, respectively. The proportions of patients with no nausea at 0­24 and 24-120 hours were also numerically similar between oral and I.V. doses.

Study 2 was a multicenter, open label, repeat cycle study performed to evaluate the safety and efficacy of single dose oral ALOXI (palonosetron hcl capsules) Capsules 0.75 mg in cancer patients receiving moderately emetogenic chemotherapy. An ALOXI (palonosetron hcl capsules) capsule was given to 217 cancer patients in 654 chemotherapy cycles one hour before the start of chemotherapy. Approximately 74% of patients also received single dose oral or intravenous dexamethasone 30 minutes before chemotherapy. Complete Response was not formally evaluated for the repeat cycle application. However, in general the antiemetic effect for the 0­24 hour interval was similar throughout the consecutively repeated cycles.

Last reviewed on RxList: 9/19/2008
This monograph has been modified to include the generic and brand name in many instances.

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