Aloxi Capsules - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Aloxi Capsules - Scientific Information

Manufacture: Eisai Inc.
Country: Canada
Condition: Nausea/Vomiting, Chemotherapy Induced, Nausea/Vomiting, Postoperative
Class: 5HT3 receptor antagonists, Antiemetic/antivertigo agents
Form: Capsules
Ingredients: palonosetron hydrochloride, Mono-glycerides and di-glycerides of capryl/capric acid, glycerin, polyglyceryl oleate, water, and butylate hydroxyanisole

Pharmaceutical Information

Drug Substance

Proper name: palonosetron hydrochloride
Chemical name: (3aS)-2-[(S)-1-Azabicyclo [2.2.2]oct-3-yl]-2,3,3a,4,5,6-hexahydro-1-oxo-1Hbenz[de]isoquinoline hydrochloride
Molecular formula and molecular mass: C19H24N2O·HCl  332.87
Structural formula:
Physicochemical properties: Palonosetron hydrochloride is a white to off-white crystalline powder. It is freely soluble in water, soluble in propylene glycol, and slightly soluble in ethanol and 2-propanol.

Clinical Trials

Aloxi Injection

Efficacy of single-dose (0.25 mg, 0.75 mg) palonosetron I.V. injection in preventing acute and delayed nausea and vomiting induced by moderately or highly emetogenic chemotherapy was studied in three Phase 3 trials. In these 3-arm double blind studies, efficacy was based on demonstrating non-inferiority of a single dose of ALOXI I.V. compared to ondansetron I.V. or dolasetron I.V. Non-inferiority criteria were met if the lower boundary of the two-sided 97.5% confidence interval for the difference in the complete response rate of palonosetron minus ondansetron or dolasetron was above -15% (non-inferiority margin 15%).

The primary endpoint was Complete Response (no emetic episode and no rescue medication) during the first 24 hours (acute phase) after chemotherapy. Secondary endpoints included Complete Response at further time periods (24-120 hours, delayed phase) and Complete Control (complete response and no more than mild nausea).

Moderately emetogenic chemotherapy

Two Phase 3, double-blind trials involving 1132 patients compared single-dose ALOXI I.V. with either single-dose I.V. ondansetron (Study 1) or I.V. dolasetron (Study 2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin, cisplatin ≤ 50 mg/m2, cyclophosphamide < 1500 mg/m2, doxorubicin > 25 mg/m2, epirubicin, irinotecan, or methotrexate. Concomitant corticosteroids were not administered prophylactically in Study 1 and were only used by 4-6% of patients in Study 2. The majority of patients in these studies were women (77%), Caucasian (65%, Hispanic: 31%) and naïve to previous chemotherapy (54%). The mean age was 55 years (18-97 years).

Table 1: Percentage of Patientsa Responding by Treatment Group and Phase in the Moderately Emetogenic Chemotherapy Study versus Ondansetron
Time Period I.V. ALOXI 0.25 mg
(n= 189)
I.V. Ondansetron
32 mg
(n= 185)
Difference
I.V. ALOXI minus
I.V. Ondansetron
Chi-square test
Complete Response [Two sided 97.5% Confidence Interval]b p-valuec
0–24 hours 81.0% 68.6% 12.4% [1.8%, 22.8%] 0.006
24–120 hours 74.1% 55.1% 19.0% [7.5%, 30.3%] <0.001
0–120 hours 69.3% 50.3% 19.0% [7.4%, 30.7%] <0.001
Complete Control [Two sided 95% Confidence Interval] p-valued
0–24 hours 76.2% 65.4% 10.8% [1.1%, 20.5%] 0.022
24–120 hours 66.7% 50.3% 16.4% [6.0%, 26.8%] 0.001
0–120 hours 63.0% 44.9% 18.1% [7.6%, 28.6%] <0.001

a Intent-to-treat cohort.

b The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates non-inferiority between Aloxi and comparator.

c Chi-square test. Significance level at α = 0.025

d Chi-square test. Significance level at α = 0.05

NS: not significant

Table 2: Percentage of Patientsa Responding by Treatment Group and Phase in the Moderately Emetogenic Chemotherapy Study versus Dolasetron
Time Period I.V. ALOXI
0.25 mg
(n= 189)
I.V. Ondansetron
100 mg
(n= 191)
Difference
I.V. ALOXI minus
I.V. Dolasetron
Chi-square test
Complete Response [Two sided 97.5% Confidence Interval]b p-valuec
0–24 hours 63.0% 52.9% 10.1% [-1.7%, 21.9%] NS
24–120 hours 54.0% 38.7% 15.3% [3.4%, 27.1%] 0.003
0–120 hours 46.0% 34.0% 12.0% [0.3%, 23.7%] 0.017
Complete Control [Two sided 95% Confidence Interval] p-valued
0–24 hours 57.1% 47.6% 9.5% [ -1%, 20%] 0.064
24–120 hours 48.1% 36.1% 12.0% [1.6%, 22.4%] 0.018
0–120 hours 41.8% 30.9% 10.9% [0.8%, 21%] 0.027

a Intent-to-treat cohort.

b The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates non-inferiority between Aloxi and comparator.

c Chi-square test. Significance level at α = 0.025

d Chi-square test. Significance level at α = 0.05

NS: not significant

The two pivotal Phase 3 studies demonstrated non-inferiority of a single I.V. dose of palonosetron 0.25 mg in the prevention of acute nausea and vomiting associated with initial course of moderately emetogenic chemotherapy, vs. I.V. ondansetron 32 mg or I.V. dolasetron 100 mg. In addition, the difference in efficacy in Study 1 was statistically significant in favour of palonosetron (p=0.006) but was not statistically significant in Study 2.

Highly emetogenic chemotherapy

A Phase 3, double-blind trial involving 667 patients compared single dose ALOXI I.V. with single-dose I.V. ondansetron given 30 minutes prior to highly emetogenic chemotherapy including cisplatin ≥60 mg/m2, cyclophosphamide, or dacarbazine. Dexamethasone, or in the event of a shortage, methylprednisolone, was co-administered prophylactically before chemotherapy in 67% of patients. Of the 667 patients, 51% were women, 60% Caucasian (Hispanic: 36%), and 59% naïve to previous chemotherapy. The mean age was 52 years (18-86 years).

Table 3: Percentage of Patientsa Responding by Treatment Group and Phase in the Moderately Emetogenic Chemotherapy Study versus Dolasetron
Time Period I.V. ALOXI
0.25 mg
(n= 223)
I.V. Ondansetron
32 mg
(n= 221)
Difference
I.V. ALOXI minus
I.V. Ondansetron
Chi-square test
Complete Response [Two sided 97.5% Confidence Interval]b p-valuec
0–24 hours 59.2% 57.0% 2.2% [-8.8%, 13.1%] NS
24–120 hours 45.3% 38.9% 6.4% [-4.6%, 17.3%] NS
0–120 hours 40.8% 33.0% 7.8% [-2.9%, 18.5%] NS
Complete Control [Two sided 95% Confidence Interval] p-valued
0–24 hours 56.5% 51.6% 4.9% [-4.8%, 14.6%] 0.298
24–120 hours 40.8% 35.3% 5.5% [-4%, 15%] 0.232
0–120 hours 37.7% 29.0% 8.7% [-0.5%, 17.9%] 0.052

a Intent-to-treat cohort.

b The study was designed to show non-inferiority. A lower bound greater than –15 % demonstrates non-inferiority between Aloxi and comparator.

c Chi-square test. Significance level at α = 0.025

d Chi-square test. Significance level at α = 0.05

NS: not significant

A single I.V. dose of palonosetron 0.25 mg was shown to be non-inferior to I.V. ondansetron 32 mg in preventing acute nausea and vomiting following highly emetogenic chemotherapy.

Subgroup analysis suggested improved efficacy of ALOXI in combination with prophylactic corticosteroids compared to ALOXI alone (see Table 4).

Table 4: Patients with a Complete Response During the First 24 Hours after Highly Emetogenic Chemotherapy by Corticosteroid Use
0-24 h Number (%) of patients with CR Difference I.V. ALOXI minus I.V. Ondansetron [Two sided 97.5% Confidence Interval] Pairwise testing*
I.V. ALOXI vs. I.V. Ondansetron
I.V. ALOXI 0.25 mg (n =223) I.V. Ondansetron 32 mg (n = 221)
With dexamethasone 97/150 (64.7%) 82/147 (55.8%) 8.9% [-4.5%; 22.2%] 0.118
Without dexamethasone 35/73 (47.9%) 44/74 (59.5%) -11.5% [-31.2%; 8.2%] 0.162

* Chi-square p-values

NS: not significant

Aloxi Capsules

Moderately emetogenic chemotherapy

In a multicentre, randomized, double-blind active control clinical trial of 635 patients set to receive moderately emetogenic cancer chemotherapy including cyclophosphamide <1500 mg/m2, doxorubicin, carboplatin, epirubicin, or idarubicin. A single-dose of 0.25 mg, 0.5 mg, or 0.75 mg oral ALOXI capsules given one hour prior to moderately emetogenic chemotherapy was compared to a single-dose of 0.25 mg ALOXI I.V. 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%), Caucasian (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). Secondary efficacy endpoint included Complete Response assessed in the delayed phase (24-120 hours) and Complete Control.

Efficacy was based on demonstrating non-inferiority of oral palonosetron doses compared to the ALOXI 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 the I.V. formulation was larger than -15%. The non-inferiority margin was 15%.

As shown in Table 8, ALOXI 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.

Table 5: Proportion of Patients Achieving Complete Response and Complete Control Post-Chemotherapy–ALOXI Capsules
Time Period Oral ALOXI 0.5 mg (N=160) I.V. ALOXI 0.25 mg (N=162) Difference Oral ALOXI minus I.V. ALOXI Comparator Chi-square test
Complete Response [Two-sided 98.3% Confidence Interval]* p-value**
0–24 h 76.3% 70.4% 5.9% [-6.5%, 18.2%] NS
24–120 h 62.5% 65.4% -2.9% [-16.3%, 10.5%] NS
0–120 h 58.8% 59.3% -0.5% [-14.2%; 13.2%] NS
Complete Control [Two-sided 95% Confidence Interval] p-value***
0–24 h 74.4% 68.5% 5.9% [ -4.6% , 16.3%] 0.245
24–120 h 56.3% 62.3% -4.0% [ -17.4% , 5.2%] 0.266
0–120 h 52.5% 56.2% -3.7% [ -15.2% , 7.8%] 0.508

* To adjust for multiplicity of treatment groups, a lower-bound of a two-sided 98.3% confidence interval was used to compare -15%, the negative value of the non-inferiority margin.

** Chi-square test, significant level at α = 0.0167 adjusted for multiple comparisons

*** Chi-square test, significant level at α = 0.05

NS: not significant

Subgroup analysis suggested improved efficacy of ALOXI in combination with prophylactic corticosteroids compared to ALOXI alone (see Table 6).

Table 6: Patients with a Complete Response During the First 24 Hours after Moderately Emetogenic Chemotherapy by Corticosteroid Use
0-24 h Number (%) of patients with CR Difference ALOXI 0.5 mg minus I.V ALOXI 0.25 mg [Two-sided 98.3% Confidence Interval] Pairwise testing*
ALOXI 0.5 mg vs. I.V ALOXI
0.25 mg
Oral ALOXI 0.5 mg (N=160) I.V. ALOXI 0.25 mg (N=162)
With dexamethasone 68/79 (86.1%) 68/82 (82.9%) 3.1% [-11.7; 18.0%] 0.581
Without dexamethasone 54/81 (66.7%) 46/80 (57.5%) 9.2 % [-10.2; 28.6%] 0.231

*Chi-square p-values

NS: not significant

Detailed Pharmacology

Human

Pharmacokinetics in repeat dosing

In a double-blind, randomized, placebo-controlled study, 12 healthy subjects received I.V. palonosetron 0.25 mg once daily for three consecutive days, and four subjects received placebo (a saline control). Palonosetron 0.25 mg I.V. daily for three consecutive days resulted in a 2.1-fold accumulation (ratio of Day 3 to Day 1 AUC0-24).

Similarly, in a multi-centre, open-label study designed to assess the safety and efficacy of palonosetron 0.25 mg I.V. on Days 1, 3 and 5 to testicular cancer patients receiving 20 mg/m2 cisplatin on Days 1 to 5 resulted in a 1.42-fold accumulation (ratio of Day 5 to Day 1 AUC0-t]. On Day 5 after the third dose, the mean Cmax, 2580 ng/L in the chemotherapy patients, was similar to the mean Cmax of 2430 ng/L observed for healthy subjects on Day 3 after consecutive 0.25 mg daily I.V. doses.

Daily dosing of palonosetron in each study produced a similar PK profile and a predictable PK profile consistent with the long plasma elimination half-life of palonosetron of approximately 40 hours.

Use in multiple cycles

Although comparative efficacy of IV and oral palonosetron in multiple cycles has not been demonstrated in controlled clinical studies, 875 patients enrolled in the three IV palonosetron phase 3 trials continued in an open label safety study and were treated with IV palonosetron 0.75mg for up to 9 additional cycles (median: 2 cycles) of chemotherapy. Moreover, 217 patients were enrolled in a multicenter, open label safety study and were treated with oral palonosetron 0.75 mg for up to 4 cycles (median: 3 cycles) of chemotherapy in a total of 654 chemotherapy cycles. The overall safety profiles were similar during all cycles in these studies.

Animal

Palonosetron is a potent and effective 5-HT3 receptor antagonist and its antiemetic actions have been clearly demonstrated in a variety of in vivo studies. It has no clinically significant action on other serotonergic receptors.

In common with other 5-HT3 receptor antagonists, palonosetron inhibits the IKr current and, at high concentrations, the INa current. These effects were demonstrated in vitro, but only at concentrations that far exceed those likely to be encountered in clinical use. They were not apparent in any in vivo study. There was evidence that palonosetron may have modest inhibitory activity at muscarinic receptor sites on sympathetic ganglia but there was no evidence of any other effect at pharmacologically relevant exposures. A number of other changes, such as convulsions in the single dose and repeat dose toxicity studies and arrhythmias in α1-adrenoreceptor activated rabbits, suggest other possible actions but these were only apparent at fatal or near-fatal dosages. There was no evidence of any cardiovascular changes in the toxicity studies.

Preliminary dog Purkinje fibre in vitro data indicated that palonosetron increased the duration of action potential in this animal preparation

Although most in vivo studies were limited to intravenous dosages of up to 1 mg/kg, this is 300-fold higher than the proposed human dose. Day 1 toxicokinetics in dogs treated intravenously at this dosage suggest that the Cmax was about 65-fold higher than the maximum expected human exposure. Exposures in the oral rat studies were probably sub-therapeutic.

In comparison to palonosetron, the two main metabolites found in humans (M9 and M4) demonstrated at least a 100-fold lower antagonistic activity at the 5-HT3 receptor in an in vitro model of isolated guinea pig ileum. In addition, they were detected only in low or trace amounts in patients receiving palonosetron. The marginal 5-HT3 antagonist activity of M4 and M9 is considered clinically non relevant.

There were significant differences in the rates and extent of metabolism in laboratory species when compared with those in humans. In man, there was relatively little metabolism of palonosetron, clearance was slow and there was an extended plasma half-life. Oral absorption was rapid in mice, rats and dogs. There was extensive metabolism in all animal species investigated and clearance was rapid. There was a significant first-pass effect in rats, dogs and primates following oral dosing, which was greatest in rats. Toxicokinetic studies suggest that this effect may be less marked in mice. The major human metabolites were present in rats and dogs; both trace human metabolites were also found in dogs, one of these was not found in rats. There was evidence that elimination mechanisms are saturated at high doses in animals, particularly rodents, and consequently exposure to palonosetron, and the human metabolites where present, was usually much greater than expected in human patients. Excretion was primarily urinary in all species including humans.

The pattern of major metabolites in rats, dogs and primates differed from each other and from humans. The plasma kinetics in monkeys are closer to those of dogs than humans. Palonosetron, but none of its metabolites, passes the blood-brain barrier in rats and was rapidly cleared from the brain, suggesting that it reaches the intended site of action and does not accumulate. There was evidence of reversible melanin binding of palonosetron or one of its metabolites in pigmented rats. No treatment-related ocular changes have been seen.

Toxicology

Single-Dose Toxicity

Deaths, in all species, were usually associated with convulsions and collapse. Other signs included inactivity, tremors, ataxia, laboured respiration, transient vocalisation in rats and emesis in dogs. There were no treatment-related signs in rats treated orally at 100 mg/kg or in dogs treated orally at up to 40 mg/kg. There were no effects associated with gender, or on body weight or food intake in any study, or on clinical pathology in dogs, and there were few necropsy observations.

A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area), equivalent to an oral dose of 500 mg/kg in rats and 100 mg/kg in dogs (7673 and 5115 times the recommended human oral dose, respectively, based on body surface area), was lethal. The maximum non-lethal dose was 20 mg/kg in both rats and dogs. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

Repeat-Dose Toxicity

Chronic intravenous administration to rats and oral treatment to mice at sub-lethal dosages was essentially without any evidence of toxicity. Treatment of dogs at marginally sublethal dosages, whether given orally or intravenously, was associated with convulsions, some other signs and, following oral treatment, a few minor clinical pathology changes, of which reduced alkaline phosphatase activity and increased cholesterol concentrations extended to lower oral dosages. There were no consistent pathology changes in dogs or mice, or in rats when treated intravenously. All of these studies were associated with high exposures to palonosetron.

In dogs deaths were clearly associated with severe signs including convulsions and the signs were generally associated with dosing and short-lived with rapid recovery. It seems likely that similar severe signs that were not observed directly were associated with the treatment-related deaths seen in mice and in intravenously treated rats.

Rats treated orally responded differently. There were numerous changes, including pathology, which extended to dosages well below those associated with increased mortality. Systemic exposure to palonosetron at the no observed adverse effect level was low compared with that following intravenous treatment to rats or dogs, although still well above that expected in human patients. Some of the deaths may have been associated with convulsions or other severe signs but it is probable that other toxic changes were more significant in rats treated orally.

Juvenile Toxicity Studies

Toxicity studies were conducted in neonatal rats and dogs. Rats were treated at Day 4 post partum by subcutaneous injection and dogs by intravenous injection from 2 weeks of age. In rats the main findings were dose-related changes at the injection sites, mainly in the high dose group (25 mg/kg/day). Other findings included reduction in body weight gains, mild anemia and increased number of lymphocytes but not histopathological changes. In neonatal dogs treated for 28 days with 6 mg/kg/day, there were no clinical or histopathological adverse effects.

Reproduction Toxicity

There was evidence that oral treatment with palonosetron at 60 mg/kg/day affected fertility in both male and female rats; this dosage is associated with histopathological changes in the seminiferous epithelium. A reduction in the number of viable foetuses in males treated intravenously at 10 mg/kg/day is not attributed to treatment.

Evidence of foetal toxicity was limited to low foetal weights in rats treated at 60 or 120 mg/kg/day during pregnancy, with an associated reduction in ossification. There was no similar effect in rabbits. In a pre- and post-natal study, there was evidence of maternal toxicity at 60 mg/kg/day. Postural changes in the F1 generation were probably a consequence of this toxicity. There was no effect on development or reproduction in the F1 generation. Juvenile toxicity studies did not show any evidence of toxicity that was not apparent in adult animals.

The no-observed-adverse-effect levels in each case were similar to or greater than those observed in repeat dose toxicity testing, suggesting that these changes only occur at exposures that significantly exceed those anticipated during clinical use.

Genotoxicity

The weight of evidence indicates that palonosetron lacks genotoxic activity. In the Salmonella (Ames) reverse mutation test, there was no evidence for mutagenic activity. There was also no evidence for mutagenic activity of palonosetron in the CHO/HGPRT forward mutation assay. An in vitro chromosome aberration assay was conducted in CHO cells in which a clastogenic effect was observed in the absence of metabolic activation and an equivocal response with metabolic activation. An additional in vitro photo-chromosome aberration assay performed in V79 cells, was negative. In an in vivo micronucleus test in mice treated intravenously at up to 10 mg/kg, there was no evidence for mutagenic or clastogenic effects. Palonosetron was also tested in the in vivo Unscheduled DNA Synthesis test in rat hepatocytes at intravenous doses of up to 30mg/kg and there was no evidence for DNA damage. Overall, palonosetron is considered non-mutagenic.

Carcinogenicity

Two carcinogenicity studies in the mouse and rat were performed. Systemic exposure to palonosetron in these studies was not linear and increased with duration (Table 7).

Table 7: Systemic Exposure to Palonosetron During Carcinogenicity Testing
Species Dosage
mg/kg/day
Time AUC, ng·h/mL Cmax, ng/mL
Male Female Male Female
Mouse 60a Day 1 5475 4623 1534 1729
Weeks 26-104 9757 5644 1788 1619
Rat 15 Day 1 39 39 19 26
Weeks 26-104 296 443 148 261
30 / 45 Day 1 362 480 153 141
Weeks 26-104 1299 3405 410 947
60 / 90 Day 1 1402 2511 427 703
Weeks 26-104 5370 10024 1420 1824

a Highest dosage = NOAEL.

In the mouse study the only statistically significant tumour incidence was in males treated at 10 mg/kg/day in respect of the combined incidence of malignant lymphoma and malignant pleomorphic lymphoma. The incidences of these common tumour types were clearly unaffected at higher dosages and the finding was not attributed to treatment. Exposure to palonosetron at the high dosage in terms of the AUCs was more than 1100-fold higher in males, and 650-fold higher in females, than found in human patients at the proposed clinical dose.

In the rat study, toxicity was apparent at all dosages although at 15 mg/kg/day this was confined to increased incidences of ungroomed coat and salivation with associated brown staining, increased liver weights and, in males only, increased accumulations of alveolar macrophages in the lungs. In addition to these, toxic changes at the highest dosage included increased mortality, reduced body weights and erythrocyte counts, increased hemosiderosis in the spleen, medullary hyperplasia in the adrenals, progressive nephropathy, clear cell foci in the liver, secretory activity and acinar hyperplasia in the mammary gland, degeneration of the tubular germinal epithelium in the testis, epithelial hyperplasia and/or cysts in the thymus, C-cell hyperplasia in the thyroid, keratin cysts in the skin and hyperplastic and inflammatory lesions in the tail.

In the rat study, there were statistically significant increased incidences of a variety of tumours affecting the adrenal, liver, mammary gland, pancreas, pituitary, skin, tail and thyroid. These tumours occurred at high doses (30 and 60 mg/kg/day) administered for 2 years. Although the underlying mechanism of palonosetron tumorigenicity is not known, it may be associated with disruption of neuroendocrine pathways.