Antiemetics and antinauseants, serotonin (5-HT3
) antagonists. ATC Code:
Pharmacology: Pharmacodynamics: Mechanism of Action:
Netupitant is a selective antagonist of human substance P/neurokinin 1 (NK1
Palonosetron is a 5-HT3
receptor antagonist with a strong binding affinity for this receptor and little or no affinity for other receptors. Chemotherapeutic substances produce nausea and vomiting by stimulating the release of serotonin from the enterochromaffin cells of the small intestine. Serotonin then activates 5-HT3
receptors located on vagal afferents to initiate the vomiting reflex.
Delayed emesis has been associated with the activation of tachykinin family neurokinin 1 (NK1
) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro
and in vivo
studies, netupitant inhibits substance P mediated responses.
Netupitant was shown to cross the blood brain barrier with a NK1 receptor occupancy of 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in striatum at 6, 24, 48, 72, and 96 hours, respectively, after administration of 300 mg netupitant.
Clinical Efficacy and Safety:
Oral administration of Akynzeo in combination with dexamethasone has been shown to prevent acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy in two separate pivotal studies.
Highly Emetogenic Chemotherapy (HEC) study:
In a multicenter, randomized, parallel, double-blind, controlled clinical study of 694 patients, the efficacy and safety of single doses of oral netupitant in combination with oral palonosetron was compared with a single oral dose of palonosetron in cancer patients receiving a chemotherapy regimen that included cisplatin (median dose = 75 mg/m2
). The efficacy of Akynzeo was assessed in 135 patients who received a single oral dose (netupitant 300 mg and palonosetron 0.5 mg) and 136 patients who received oral palonosetron 0.5 mg alone.
Treatment regimens for the Akynzeo and the palonosetron 0.5 mg arms are displayed in Table 1. (See Table 1.)
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The primary efficacy endpoint was complete response (CR) rate (defined as no emetic episodes, no rescue medication) within 120 hours (overall phase) after the start of the highly emetogenic chemotherapy administration.
A summary of the key results from this study is shown in Table 2. (See Table 2.)
Click on icon to see table/diagram/image
Moderately Emetogenic Chemotherapy (MEC) study: In a multicenter, randomized, parallel, double-blind, active-controlled, superiority study, the efficacy and safety of a single oral dose of Akynzeo was compared with a single oral dose of palonosetron 0.5 mg in cancer patients scheduled to receive the first cycle of an anthracycline and cyclophosphamide regimen for the treatment of a solid malignant tumor. At the time of the study, anthracycline-cyclophosphamide containing chemotherapy regimens were considered to be moderately emetogenic. Recent guidance has updated these regimens to highly emetogenic.
All patients received a single oral dose of dexamethasone. (See Table 3.)
Click on icon to see table/diagram/image
After completion of cycle 1, patients had the option to participate in a multiple-cycle extension, receiving the same treatment as assigned in cycle 1. There was no pre-specified limit of the number of repeat consecutive cycles for any patient. A total of 1450 patients (Akynzeo n=725; Palonosetron n=725) received study medication. Of these, 1438 patients (98.8%) completed cycle 1 and 1286 patients (88.4%) continued treatment in the multiple-cycle extension. A total of 907 patients (62.3%) completed the multiple-cycle extension up to a maximum of eight treatment cycles. A total of 724 patients (99.9%) were treated with cyclophosphamide. All patients were additionally treated with either doxorubicin (68.0%) or epirubicin (32.0%).
The primary efficacy endpoint was the CR rate in the delayed phase, 25-120 hours after the start of the chemotherapy administration.
A summary of the key results from this study is shown in Table 4. (See Table 4.)
Click on icon to see table/diagram/image
Patients continued into the Multiple-Cycle extension for up to 7 additional cycles of chemotherapy. Antiemetic activity of Akynzeo was maintained throughout repeat cycles for those patients continuing in each of the multiple cycles.
The impact of nausea and vomiting on patients' daily lives was assessed using the Functional Living Index–Emesis (FLIE). The proportion of patients with Overall no impact on daily life was 6.3% higher (p value =0.005) in the Akynzeo group (78.5%) than in the palonosetron group (72.1%).
Multiple-cycle safety study in patients receiving either Highly Emetogenic Chemotherapy or Moderately Emetogenic Chemotherapy:
In a separate study, a total of 413 patients undergoing initial and repeat cycles of chemotherapy (including carboplatin, cisplatin, oxaliplatin, and doxorubicin regimens), were randomized to receive either Akynzeo (n=309) or aprepitant and palonosetron (n=104). Safety and efficacy were maintained throughout all cycles.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Akynzeo in all subsets of the paediatric population in prevention of acute and delayed nausea and vomiting associated with highly emetogenic cisplatin-based and moderately emetogenic cancer chemotherapy (see Dosage & Administration on paediatric use).
Netupitant: Absolute netupitant bioavailability data are not available in humans; based on data from two studies with intravenous netupitant, the bioavailability in humans is estimated to be greater than 60%.
In single dose oral studies, netupitant was measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations followed a first order absorption process and reached Cmax
in approximately 5 hours. There was a supra-proportional increase in Cmax
and AUC parameters for doses from 10 mg to 300 mg.
In 82 healthy subjects given a single oral dose of netupitant 300 mg, maximum plasma netupitant concentration (Cmax
) was 486 ±268 ng/mL (mean ± SD) and median time to maximum concentration (Tmax
) was 5.25 hours, the AUC was 15032 ± 6858 h.ng/mL. In a pooled analysis, females had a higher netupitant exposure compared to males; there was a 1.31-fold increase in Cmax
, a 1.02 fold increase for AUC and a 1.36 fold increase in half-life.
increased by 1.1 fold and 1.2 fold, respectively, after a high fat meal.
Palonosetron: Following oral administration, palonosetron is well absorbed with its absolute bioavailability reaching 97%. After single oral doses using buffered 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 mcg/kg in healthy subjects.
In 36 healthy male and female subjects given a single oral dose of 0.5 mg palonosetron, maximum plasma concentration (Cmax
) was 0.81 ± 1.66 ng/mL (mean ± SD) and time to maximum concentration (Tmax
) was 5.1 ± 1.7 hours. In female subjects (n=18), the mean AUC was 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. A high fat meal did not affect the Cmax
and AUC of oral palonosetron.
Netupitant: After a single oral 300 mg dose administration in cancer patients, netupitant disposition was characterised by a two compartment model with an estimated median systemic clearance of 20.5 L/h and a large distribution volume in the central compartment (486 L). Human plasma protein binding of netupitant and its two major metabolites M1 and M3 is > 99% at concentrations ranging from 10 to 1500 ng/mL. The third major metabolite, M2, is > 97% bound to plasma proteins.
Palonosetron: Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. Approximately 62% of palonosetron is bound to plasma proteins.
Netupitant: Three metabolites have been detected in human plasma at netupitant oral doses of 30 mg and higher (the desmethyl derivative, M1; the N-oxide derivative, M2; the OH-methyl derivative, M3). In vitro
metabolism studies have suggested that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are involved in the metabolism of netupitant. After administration of a single oral dose of 300 mg netupitant, mean plasma netupitant/plasma radioactivity ratios ranged from 0.13 to 0.49 over 96 h post-dose. The ratios were time dependent with values decreasing gradually beyond 24 h post-dose, indicating that netupitant is being rapidly metabolized. Mean Cmax
was approximately 11%, 47% and 16% of the parent for M1, M2 and M3 respectively; M2 had the lowest AUC relative to the parent (14%) whereas M1 and M3 AUC were approximately 29% and 33% of the parent, respectively. M1, M2 and M3 metabolites were all shown to be pharmacologically active in an animal pharmacodynamic model, where M3 was most potent and M2 least active.
Palonosetron: 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.
Netupitant: Following administration of a single dose of Akynzeo, netupitant is eliminated from the body in a multiexponential fashion, with an apparent mean elimination half-life of 88 hours in cancer patients.
Renal clearance is not a significant elimination route for netupitant-related entities. The mean fraction of an oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95% and 70.7% of the radioactive dose was recovered in the urine and faeces, respectively.
Approximately half the radioactivity administered orally as [14C]-netupitant was recovered from urine and faeces within 120 h of dosing. Elimination via both routes was estimated to be complete by Day 29-30 post-dose.
Palonosetron: 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 faeces. The amount of unchanged palonosetron excreted in the urine represented approximately 40% of the administered dose. In healthy subjects given palonosetron capsules 0.5 mg, the terminal elimination half-life (t½
) of palonosetron was 37 ± 12 hours (mean ± SD), and in cancer patients, t½
was 48 ± 19 hours. After a single dose of approximately 0.75 mg intravenous palonosetron, the total body clearance of palonosetron in healthy subjects was 160 ± 35 mL/h/kg (mean ± SD) and renal clearance was 66.5± 18.2 mL/h/kg.
Hepatic Impairment: Netupitant: Maximum concentrations and total exposure of netupitant were increased in subjects with mild (n=8), moderate (n=8), and severe (n=2) hepatic impairment compared to matching healthy subjects, although there was pronounced individual variability in both hepatically-impaired and healthy subjects. Exposure to netupitant (Cmax
) compared to matching healthy subjects was 11%, 28% and 19% higher in mild and 70%, 88% and 143% higher in moderate hepatically-impaired subjects, respectively. As such, no dosage adjustment is necessary for patients with mild to moderate hepatic impairment. Limited data exist in patients with severe hepatic impairment (Child Pugh score ≥9).
Palonosetron: Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. While the terminal elimination half-life and mean systemic exposure of palonosetron is increased in the subjects with severe hepatic impairment, this does not warrant dose reduction.
Renal impairment: Netupitant: No specific studies were performed to evaluate netupitant in patients with renal impairment. In the ADME trial, less than 5% of all netupitant-related material was excreted in urine and less than 1% of the netupitant dose was eliminated unchanged in the urine and therefore any accumulation of netupitant or metabolites after a single dose would be negligible. Furthermore, the population PK study showed no correlation between PK parameters of netupitant and markers of renal dysfunction.
Palonosetron: Mild to moderate renal impairment does not significantly affect palonosetron PK parameters. Total systemic exposure to intravenous palonosetron increased by approximately 28% in patients with severe impairment relative to healthy subjects. In a population PK study, patients with a reduced creatinine clearance (CLCR
) also had a reduced palonosetron clearance, but this reduction would not result in a significant change in palonosetron exposure.
Therefore, Akynzeo can be administered without dosage adjustment in patients with renal impairment.
Neither netupitant nor palonosetron have been evaluated in patients with end-stage renal disease.
Toxicology: Preclinical safety data:
Palonosetron: Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure, indicating little relevance to clinical use. Non-clinical studies indicate that palonosetron, only at very high concentrations, may block ion channels involved in ventricular de- and re-polarisation and prolong action potential duration. Degeneration of seminiferous epithelium was associated with palonosetron following a one month oral repeat dose toxicity study in rats. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Only limited data from animal studies are available regarding the placental transfer (see Use in Pregnancy & Lactation). Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 15 times the human therapeutic exposure) applied daily for two years caused an increased rate of liver tumours, endocrine neoplasms (in thyroid, pituitary, pancreas, adrenal medulla) and skin tumours in rats but not in mice. The underlying mechanisms are not fully understood, but because of the high doses employed and since the medicinal product is intended for single application in humans, these findings are not considered relevant for clinical use.
Netupitant and combination with palonosetron:
Effects in non-clinical studies based on safety pharmacology and single and repeated dose toxicity were observed only at exposures considered in excess of the maximum human exposure, indicating little relevance to clinical use. Phospholipidosis (foamy macrophages) has been observed with the administration of netupitant after repeated administration in rats and dogs. The effects were reversible or partially reversible after the recovery period. The significance of these findings in humans is unknown.
Non-clinical studies indicate that netupitant and its metabolites and the combination with palonosetron only at very high concentrations may block ion channels involved in ventricular de- and re- polarisation and prolong action potential duration. Reproductive studies in animals with netupitant do not indicate direct or indirect harmful effects with respect to fertility, parturition or postnatal development. An increased incidence of positional foetal abnormalities of the limbs and paws, fused sternebrae and agenesis of accessory lung lobe were observed following daily administration of netupitant in rabbits at 10 mg/kg/day and higher during the period of organogenesis. In a pilot dose range finding study in rabbits, cleft palate, microphtalmia and aphakia were observed in four foetuses from one litter in the 30 mg/kg/day group. The relevance of these findings in humans is unknown. No data from animal studies with netupitant are available regarding placental transfer and lactation. Netupitant is not mutagenic.