Akynzeo 300 mg + 0.5 mg 1 pc. capsules

- Prevention of acute and delayed nausea and vomiting in adults caused by highly emetogenic chemotherapy based on cisplatin;
- Prevention of acute and delayed nausea and vomiting in adults caused by moderate chemotherapy.

For oral use. The capsule should be swallowed whole, regardless of food intake.
Adults
Take one capsule approximately one hour before the start of each chemotherapy cycle. The recommended oral dose of dexamethasone should be reduced by 50% when used concurrently with Akynzeo (see dosing regimen studies in the "Clinical Efficacy and Safety" section).
Elderly patients
Dose adjustment for elderly patients is not required.
Patients over 75 years of age should use the medication with caution due to the prolonged half-life of the active substances and limited experience in this patient group.
Children
The efficacy and safety of Akynzeo in children have not been established.
Patients with renal impairment
Dose adjustment in patients with renal insufficiency from mild to severe is not required.
Renal excretion of netupitant is minimal. In patients with mild or moderate renal insufficiency, the pharmacokinetic parameters of palonosetron do not change significantly. The overall systemic exposure following intravenous administration of palonosetron in patients with severe renal insufficiency compared to healthy volunteers increased by approximately 28%. The pharmacokinetics of palonosetron and netupitant have not been studied in patients with end-stage renal disease requiring hemodialysis; data on the efficacy and safety of Akynzeo in such patients are not available. Therefore, the use of Akynzeo in these patients is not recommended.
Patients with hepatic impairment
Dose adjustment in patients with mild to moderate hepatic insufficiency is not required (Child-Pugh classification score 5-8). There are limited data for patients with severe hepatic insufficiency (Child-Pugh classification score ≥9). Since the use of the medication in patients with severe hepatic insufficiency may be associated with increased exposure to netupitant, Akynzeo should be used with caution in these patients.

1 capsule contains:
netupitant tablets 100 mg (3 pcs.),
soft gelatin capsule of palonosetron 0.5 mg (1 pc.).
Composition per 1 netupitant tablet:
Active ingredient: netupitant 100 mg
Excipients: microcrystalline cellulose (pH 101) 20.5 mg, lauryl sucrose ester 10.0 mg, povidone K-30 7.0 mg, purified water, sodium croscarmellose 3.0 mg, silicon dioxide (colloidal) 3.0 mg, sodium stearyl fumarate 1.0 mg, magnesium stearate 0.5 mg.
Composition per 1 soft gelatin capsule of palonosetron:
Active ingredient: palonosetron hydrochloride 0.56 mg (calculated as palonosetron 0.50 mg)
Excipients (contents): glycerol monocaprylate (type I) 62.20 mg, glycerol 3.37 mg, polyglycerol oleate 0.87 mg, purified water 2.93 mg, butylated hydroxyanisole (BHA) 0.07 mg.
Capsule shell: gelatin (type 195) 34.10 mg; sorbitol, special mixture 23.60 mg; titanium dioxide 0.18 mg.
Composition of the gelatin capsule shell:
body: gelatin - 56.4480 mg, titanium dioxide - 1.1520 mg;
cap: gelatin 36.9664 mg, titanium dioxide 0.1280 mg, iron oxide yellow dye 0.7826 mg, iron oxide red dye 0.5230 mg.
Composition of ink 10A1 black: iron oxide black dye, propylene glycol.

Hard gelatin capsules No. 0 with a white body and a brown cap, opaque, with the inscription in black ink "НЕ1" on the body.
Contents of the capsule:

• three round flat tablets of nearly white color with barely noticeable marbling, brownish and grayish specks are allowed, with a bevel on both sides;

• a soft spherical capsule of light yellow color, opaque, with a seam, containing a clear solution of light yellow color.

• Increased sensitivity to active substances or any other component of the drug.
• Age under 18 years.
• Pregnancy.

WITH CAUTION
Should be used with caution in patients with a tendency to prolong the QT interval (see "Special Instructions" section).

USE DURING PREGNANCY AND LACTATION
Planning for Pregnancy
Women planning to become pregnant are advised to take a pregnancy test before starting the medication to ensure that they are not pregnant. Contraceptives should also be used for 1 month after completing Akynzeo therapy.
Pregnancy
Palonosetron
There is no data on the effects of palonosetron in pregnant women. Animal studies have not shown direct or potential toxic effects of palonosetron on reproductive function.
Netupitant
There is no data on the effects of netupitant in pregnant women. Animal studies have shown toxic effects of netupitant on reproductive function, including the development of teratogenic effects in rabbits.
Thus, the use of Akynzeo during pregnancy is contraindicated.
Lactation
It is unknown whether palonosetron or netupitant are excreted in breast milk. There is a potential risk to the newborn.
The use of Akynzeo during breastfeeding is not recommended.
After completing therapy with Akynzeo, it is advisable to refrain from breastfeeding for another 1 month.

Constipation
Since palonosetron may increase intestinal transit time, patients suffering from constipation or with signs of subacute intestinal obstruction should be monitored after administration. Cases of constipation with fecal impaction requiring hospitalization have been reported after administration of palonosetron, 0.75 mg.

Serotonin Syndrome
Cases of serotonin syndrome have been reported with the use of 5-HT3 antagonists as monotherapy or in combination with other serotonergic medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Appropriate monitoring of patients for serotonin syndrome is recommended.

QT Interval Prolongation Syndrome
An ECG study was conducted in healthy male and female volunteers who received netupitant orally at doses of 200 or 600 mg, in combination with palonosetron, 0.5 mg or 1.5 mg, respectively. The study did not reveal clinically significant effects on ECG parameters: the highest point estimate for placebo and baseline-corrected QTc interval was 7.0 ms (one-sided upper 95% confidence limit 8.8 ms), observed 16 hours after administration of supratherapeutic doses (600 mg netupitant and 1.5 mg palonosetron). The upper 95% confidence limit for the point estimate of placebo and baseline-corrected QTcI was within 10 ms at all time points over 2 days after administration of the investigational drug.
However, since Akynzeo contains a 5-HT3 receptor antagonist, caution should be exercised when co-administering with medications that prolong the QT interval in patients diagnosed with or at risk of developing QT interval prolongation. These conditions include patients with a personal or family history of QT interval prolongation, with electrolyte disturbances, congestive heart failure, bradyarrhythmia, conduction disorders, and patients taking antiarrhythmic medications or other drugs that lead to QT interval prolongation or electrolyte disturbances. Hypokalemia and hypomagnesemia should be treated prior to administration of the drug.
This medication should not be used for the treatment and prevention of nausea and vomiting after chemotherapy unless it is related to the next course of chemotherapy.
Caution should be exercised when administering the drug to patients with severe hepatic insufficiency, as data for such patients is limited.
This drug should be used with caution in patients taking orally active substances that are primarily metabolized by CYP3A4 and have a narrow therapeutic range, such as cyclosporine, tacrolimus, sirolimus, everolimus, alfentanil, dihydroergotamine, ergotamine, fentanyl, and quinidine.

Chemotherapeutic agents that are substrates for CYP3A4
Netupitant is a moderate inhibitor of CYP3A4 and may increase the exposure of chemotherapeutic agents that are substrates for CYP3A4, such as docetaxel. Therefore, patients should be monitored for increased toxicity of chemotherapeutic agents that are CYP3A4 substrates, including irinotecan. Additionally, netupitant may also affect the efficacy of chemotherapeutic agents that require activation through CYP3A4 metabolism.

Excipients
Akynzeo contains sorbitol and sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medication.

The product may contain traces of soy lecithin. Therefore, patients with hypersensitivity to peanuts or soy should closely monitor for signs of allergic reactions.

EFFECT ON ABILITY TO DRIVE AND OPERATE MACHINERY
Akynzeo has a moderate effect on the ability to drive and operate machinery. However, since the medication may cause dizziness, drowsiness, or fatigue, patients should refrain from driving or operating machinery if such symptoms occur.

Safety Profile Summary
Among the side effects associated with the use of Akynzeo, the most frequently reported were headache (3.6%), constipation (3.0%), and fatigue (1.2%). None of these cases were serious.
Data on side effects in tabular form
The safety profile of Akynzeo was evaluated in 1169 cancer patients receiving at least one course of highly or moderately emetogenic chemotherapy in three double-blind active-controlled studies. Side effects were more common with Akynzeo than with palonosetron 0.5 mg. Data are presented in Table 5 by organ system classes and frequency according to MedDRA terminology.
Side effects are classified by frequency as:
very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown (the available data do not allow for an assessment).Table 5: Side effects associated with the use of AkynzeoOrgan System Class | Common | Uncommon | Rare --- | --- | --- | --- Infections and infestations | Cystitis | - | - Blood and lymphatic system disorders | Neutropenia | Leukopenia | Leukocytosis Metabolism and nutrition disorders | Decreased appetite | Hypokalemia | - Psychiatric disorders | Insomnia | Acute psychosis | Mood changes; Sleep disturbances Nervous system disorders | Headache | Nausea | Hypoesthesia Eye and ear disorders | Dizziness | Conjunctivitis | Blurred vision Cardiovascular system disorders | First-degree atrioventricular block | Arrhythmia | Cardiomyopathy; Second-degree atrioventricular block; Heart conduction disorder; Bundle branch block; Mitral valve insufficiency; Myocardial ischemia; Ventricular extrasystole Hematopoietic system disorders | Hypertension | Hypotension | - Respiratory system disorders | Hiccups | - | - Gastrointestinal disorders | Constipation | Abdominal pain | Dysphagia; Diarrhea; Coated tongue; Dyspepsia; Flatulence; Nausea Skin and subcutaneous tissue disorders | Alopecia | Urticaria | - Musculoskeletal and connective tissue disorders | Back pain | - | - General disorders | Fatigue | Asthenia | Fever; Chest pain; Altered taste Study cases | Increased liver transaminases | Increased blood bilirubin | Increased blood alkaline phosphatase; Increased blood creatine phosphokinase; Increased blood creatinine; ST segment depression on ECG; Prolonged QT interval on ECG; ST-T segment deviation on ECG; Increased troponin levelsDescription of individual side effects No frequent side effects related to netupitant, the new component of the combination drug, were observed, as their frequency is similar to that of side effects from palonosetron. Reports of eye swelling, dyspnea, and myalgia with palonosetron use were noted; however, these do not pertain to the Akynzeo product itself. All these reactions were rare. Very rare cases of anaphylaxis, anaphylactic/anaphylactoid reactions, and shock have been reported with post-marketing intravenous use of palonosetron.There is no specific information on overdose with Akynzeo during therapy. In clinical studies, netupitant was used up to 600 mg and palonosetron up to 6 mg, and this did not raise safety concerns. In case of overdose, the use of the medication should be discontinued, the patient should be monitored, and standard supportive treatment should be applied. Due to the antiemetic activity of netupitant and palonosetron, vomiting induced by medications may be ineffective. Dialysis studies have not been conducted. However, due to the high volume of distribution of netupitant and palonosetron, dialysis in the case of overdose may be ineffective.When used concurrently with Akynzeo and other CYP3A4 inhibitors, the plasma concentration of netupitant may increase. When used concurrently with medications that suppress CYP3A4 activity, the plasma concentration of netupitant may decrease, potentially leading to reduced efficacy. Akynzeo may increase the plasma concentration of concomitant medications whose metabolism involves CYP3A4. In humans, netupitant is primarily eliminated through the liver, involving CYP3A4 with minimal renal excretion. Netupitant is a substrate and a moderate inhibitor of the CYP3A4 isoenzyme when administered at 300 mg.Palonosetron is eliminated from the body both renally and metabolically, primarily via CYP enzymes, mainly CYP2D6, and to a lesser extent CYP3A4 and CYP1A2 isoenzymes. Based on in vitro studies, palonosetron neither inhibits nor stimulates cytochrome P450 isoenzymes at clinically relevant concentrations.Netupitant and palonosetron when taken orally: No clinically significant pharmacokinetic interactions were observed.CYP3A4 substrates: Dexamethasone The concurrent administration of 300 mg netupitant with dexamethasone (day 1 - 20 mg, days 2-4 - 8 mg twice daily) significantly increases the concentration of the latter depending on the time and dosage. The area under the curve of dexamethasone - AUC0-24 (day 1), AUC24-36 (day 2), AUC84-108, and AUC84-? (day 4) increased by 2.4 times when administered with netupitant, 300 mg. The pharmacokinetic profile of netupitant remained unchanged when combined with dexamethasone. Therefore, the dexamethasone dosage should be reduced by approximately 50% when taken concurrently with Akynzeo.Other chemotherapy drugs (docetaxel, etoposide, cyclophosphamide): The concentration of docetaxel and etoposide increased by 37% and 21%, respectively, when taken concurrently with Akynzeo. No such effect was observed with cyclophosphamides when taken concurrently with netupitant.Oral contraceptives: Akynzeo, when taken concurrently with 60 mcg of ethinyl estradiol, did not significantly affect the AUC of the latter. When taken with 300 mcg of levonorgestrel, the AUC of levonorgestrel increased by 1.4 times. No effects on the efficacy of hormonal contraceptives were observed when taken concurrently with Akynzeo. The pharmacokinetics of netupitant and palonosetron remained unchanged.Erythromycin and midazolam The plasma concentrations of erythromycin and midazolam increased by 1.3 and 2.4 times, respectively, when taken concurrently with netupitant. This was not considered a clinically significant effect. The pharmacokinetic profile of netupitant remained unchanged. The potential effect of increased concentrations of midazolam or other benzodiazepines, whose metabolism involves CYP3A4 (alprazolam, triazolam), should be considered when co-administering with Akynzeo.Serotonin medications (SSRIs and SNRIs) There have been reports of serotonin syndrome following the concurrent use of 5-HT3 antagonists and other serotonergic medications (including SSRIs and SNRIs).Other medications affecting the pharmacokinetics of Akynzeo Netupitant is primarily eliminated via CYP3A4; therefore, concurrent use with medications that inhibit or induce CYP3A4 activity may affect the plasma concentration of netupitant. Caution is recommended when used with strong CYP3A4 inhibitors (e.g., ketoconazole), and concurrent use with strong CYP3A4 inducers should be avoided (e.g., rifampicin).Effect of ketoconazole and rifampicin Concurrent administration of CYP3A4 inhibitors - ketoconazole with Akynzeo increased the AUC of netupitant by 1.8 times and Cmax by 1.3 times compared to Akynzeo alone. Co-administration with ketoconazole does not affect the pharmacokinetics of palonosetron. Therefore, caution should be exercised when co-administering strong CYP3A4 inhibitors (e.g., ketoconazole) with Akynzeo, and co-administration with strong CYP3A4 inducers (e.g., rifampicin) should be avoided.Other medications The interaction of Akynzeo with drugs that are substrates of the P-glycoprotein transporter is unlikely. Netupitant is not a substrate of the P-glycoprotein transporter. When netupitant was administered on day 8 in a 12-day regimen of digoxin, no changes in the pharmacokinetics of digoxin were observed. Inhibition of the breast cancer resistance protein (BCRP) and glucuronidation by the UGT2B7 isoenzyme by netupitant is unlikely. In vitro data show that netupitant inhibits the UGT2B7 isoenzyme, but the extent of this phenomenon in clinical studies is not presented. Caution is recommended when co-administering netupitant with oral substrates of this enzyme (e.g., zidovudine, valproic acid, morphine).In vitro data show that netupitant inhibits the efflux transporter breast cancer resistance protein (BCRP). Clinical data are not presented. In vitro data indicate that netupitant is a P-glycoprotein inhibitor. In a study in healthy volunteers, netupitant did not affect the concentration of digoxin, a P-glycoprotein substrate, but increased the mean maximum concentration by 1.09 times [90% CI 0.9 - 1.31]. It is possible that this effect may have greater clinical significance in cancer patients with impaired renal function. Therefore, caution is recommended when co-administering netupitant with digoxin or other P-glycoprotein substrates, such as dabigatran or colchicine.

Mechanism of Action
Netupitant is a selective antagonist of neurokinin-1 (NK1) substance P receptors.
Palonosetron is a 5-HT3 receptor antagonist with high affinity for this receptor and no binding to other receptors. Chemotherapeutic agents induce nausea and vomiting by stimulating the release of serotonin from enterochromaffin cells in the small intestine. Serotonin then activates 5-HT3 receptors located on vagal afferents to initiate the vomiting reflex.
Delayed vomiting has been associated with the activation of tachykinin NK1 receptors (distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant suppresses the urge to vomit via substance P.

Netupitant crosses the blood-brain barrier with NK1 receptors at 92.5%, 86.5%, 85.0%, 78.0%, and 76.0% in the striatum at 6, 24, 48, 72, and 96 hours, respectively, after administration of 300 mg of netupitant.

Clinical Efficacy and Safety
Oral administration of Akynzeo in combination with dexamethasone prevents episodes of acute and delayed nausea and vomiting in patients undergoing highly and moderately emetogenic chemotherapy in two separate pivotal studies.

Study of Highly Emetogenic Chemotherapy
In a multicenter, randomized, parallel, double-blind controlled clinical trial involving 694 patients, the efficacy and safety of a single oral dose of Akynzeo were compared with a single dose of palonosetron in cancer patients undergoing chemotherapy with cisplatin (mean dose 75 mg/m2). The efficacy of Akynzeo was evaluated in 135 patients who received a single dose (netupitant 300 mg + palonosetron 0.5 mg) and in 136 patients who received palonosetron 0.5 mg.
The dosing regimen of Akynzeo and palonosetron 0.5 mg for emetogenic chemotherapy is reflected in Table 1.
Table 1: Dosing Regimen of Oral Medications for Emetogenic Chemotherapy

Dosing Regimen Day 1 Day 2-4
Akynzeo Akynzeo (netupitant 300 mg + palonosetron 0.5 mg)
Dexamethasone 12 mg Dexamethasone 8 mg once daily
Palonosetron Palonosetron 0.5 mg
Dexamethasone 20 mg Dexamethasone 8 mg twice daily
The primary endpoint for efficacy was complete remission (no vomiting episodes, no need for rescue medication) within 120 hours after the start of highly emetogenic chemotherapy. A summary of the study results is shown in Table 2.
Table 2: Proportion of Patients Receiving Cisplatin Chemotherapy (Groups and Phases)

Akynzeo N=135
% Palonosetron 0.5 mg N=136
% p-value
Primary Efficacy Endpoint
Complete Response Complete Phase
89.6 76.5 0.004
Secondary Efficacy Endpoint
Complete Response Acute Phase Delayed Phase
98.5 90.4
89.7 80.1
0.007
0.018
Absence of Vomiting Acute Phase Delayed Overall
98.5 91.9
91.1 89.7
80.1 76.5
0.007
0.006
0.001
Absence of Nausea Acute Phase Delayed Overall
98.5 90.4
89.6 93.4
80.9 79.4
0.050
0.004
0.021
Note:
Acute Phase: 0 - 24 hours after cisplatin therapy
Delayed Phase: 25 - 120 hours after cisplatin therapy
Overall: 1-120 hours after cisplatin therapy

Study of Moderately Emetogenic Chemotherapy in Cancer Patients
In a multicenter, randomized, parallel, double-blind, actively controlled, superiority clinical trial, the efficacy and safety of a single oral dose of Akynzeo (netupitant 300 mg + palonosetron 0.5 mg) were compared with a single dose of palonosetron 0.5 mg in cancer patients receiving the first cycle of chemotherapy with anthracyclines and cyclophosphamides for the treatment of solid malignant tumors. During the study, anthracycline-cyclophosphamide therapy was considered moderately emetogenic. In recent studies, it is regarded as highly emetogenic. All patients received single doses of dexamethasone.

Table 3: Dosing Regimen of Oral Medications for Moderately Emetogenic Therapy
Dosing Regimen Day 1 Day 2-3
Akynzeo Akynzeo (netupitant 300 mg

• palonosetron 0.5 mg) Dexamethasone 12 mg No therapy
Palonosetron Palonosetron 0.5 mg
Dexamethasone 20 mg No therapy

After completing the first cycle, patients were offered participation in a multicycle study repeating the first cycle. There were no restrictions on the number of cycles. A total of 1450 patients participated in the study (Akynzeo n=725; palonosetron n=725). Of these, 1438 patients (98.8%) completed the first cycle, and 1286 (84.4%) continued participation in the multicycle study. A total of 907 patients (62.3%) completed the multicycle study, with a maximum of 8 cycles. A total of 724 patients (99.9%) received cyclophosphamide therapy. All patients additionally received doxorubicin (68.0%) or epirubicin (32.0%).
The primary efficacy criterion was the percentage of complete responses in the delayed phase, 25-120 hours after the start of chemotherapy. The results of this study are shown in Table 4.
Table 4: Proportion of Patients Receiving Anthracycline and Cyclophosphamide-Based Chemotherapy by Treatment Groups and Phases, Cycle 1.
Akynzeo Palonosetron, 0.5 mg p-value *
N=724 N=725
% %
Primary Efficacy Endpoint
Complete Response
Delayed Phase† 76.9 69.5 0.001
Primary Secondary Efficacy Endpoints
Complete Response
Acute Phase‡ 88.4 85.0 0.047
Overall Phase§ 74.3 66.6 0.001
Absence of Vomiting
Acute Phase 90.9 87.3 0.025
Delayed Phase 81.8 75.6 0.004
Overall Phase 79.8 72.1

Absorption
Netupitant
Data on the absolute bioavailability of netupitant in humans are lacking. According to two studies (netupitant, intravenously), the bioavailability in humans is over 60%.

In studies using single oral doses, netupitant was detected in plasma from 15 minutes to 3 hours after administration. The change in drug concentration in plasma represents a first-order absorption process and reaches Cmax approximately 5 hours after administration. A superproportional increase in Cmax and AUC parameters was observed for doses ranging from 10 mg to 300 mg.
In 82 healthy volunteers receiving a single dose of 300 mg netupitant, the maximum plasma concentration (Cmax) was 486 ± 268 ng/ml (mean ± standard deviation), and the mean time to reach maximum concentration (Tmax) was 5.25 hours, with AUC being 15032 ± 6858 h.ng/ml.
In a pooled analysis, women exhibited a stronger effect of netupitant compared to men; a 1.31-fold increase in Cmax and a 1.02-fold increase in AUC were recorded, as well as a 1.36-fold increase in the half-life.
AUC0-? and Cmax of netupitant increased by 1.1 and 1.2 times, respectively, after consumption of a high-fat meal.
Palonosetron
When taken orally, palonosetron is well absorbed, with an absolute bioavailability of 97%. After a single oral dose using a buffered solution, the mean maximum concentration of palonosetron (Cmax) and the area under the concentration-time curve (AUC 0-?) were proportional to the dose in the range of 3.0 to 80 mcg/kg in healthy volunteers.
In 36 healthy men and women receiving a single dose of 0.5 mg palonosetron, the maximum plasma concentration (Cmax) was 0.81 ± 1.66 ng/ml (mean ± standard deviation) and the time to maximum concentration (Tmax) was 5.1 ± 1.7 hours. In female patients (n = 18), the mean AUC was 35% higher, and the mean Cmax was 26% higher than in male patients (n = 18).
In 12 cancer patients who received a single dose of 0.5 mg palonosetron one hour before chemotherapy, Cmax was 0.93 ± 0.34 ng/ml and Tmax was 5.1 ± 5.9 hours. AUC in cancer patients was 30% higher than in healthy volunteers.
High-fat food did not affect Cmax and AUC when palonosetron was taken orally.

Distribution
Netupitant
After a single oral dose of 300 mg netupitant in cancer patients, the distribution of netupitant is characterized by a two-compartment model with an estimated mean total clearance of 20.5 L/h and a large volume of distribution in the central compartment (486 L). Binding of netupitant and its two main metabolites M1 and M3 to human plasma protein is >99% at concentrations ranging from 10 to 1500 ng/ml. The third main metabolite M2 is >97% bound to plasma proteins.
Palonosetron
Palonosetron has a volume of distribution of approximately 8.3 ± 2.5 L/kg. About 62% of palonosetron is bound to plasma proteins.

Metabolism
Netupitant
Three metabolites were detected in plasma after oral doses of netupitant of 30 mg and higher (desmethyl derivative, M1; N-oxide derivative, M2; OH-methyl derivative, M3). In vitro metabolism studies showed that CYP3A4 and, to a lesser extent, CYP2D6 and CYP2C9 are involved in the metabolism of netupitant. After administration of a single dose of 300 mg netupitant, the mean ratios of radioactivity netupitant/plasma ranged from 0.13 to 0.49 over 96 hours post-administration. The ratio is time-dependent with gradually decreasing values over 24 hours after administration, indicating that netupitant is rapidly metabolized. The mean Cmax was approximately 11%, 47%, and 16% of the parent compound for M1, M2, and M3, respectively; M2 had the lowest AUC relative to the parent compound (14%), while AUC for M1 and M3 was approximately 29% and 33% of the parent compound, respectively. Metabolites M1, M2, and M3 demonstrated pharmacological activity in a pharmacodynamic animal model, with M3 being the most active and M2 the least active.
Palonosetron
Palonosetron is eliminated through several pathways; approximately 50% is metabolized to form two main metabolites: N-oxide palonosetron and 6-S-hydroxy palonosetron. Each of these metabolites has less than 1% of the 5-HT3 antagonist activity of palonosetron. In vitro metabolism studies showed that isoenzymes CYP2D6 and, to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism of palonosetron. However, clinical pharmacokinetic studies did not reveal significant differences between fast and slow metabolizers of CYP2D6 substrates.

Excretion
Netupitant
After administration of a single dose of Akynzeo, netupitant is eliminated from the body via a multi-exponential pathway, with a mean half-life of 88 hours in cancer patients. Renal clearance is not a significant route of elimination for substances associated with netupitant. The average fraction of the oral dose of netupitant excreted unchanged in urine is less than 1%; a total of 3.95% and 70.7% of the radioactive dose were recovered in urine and feces, respectively.
Approximately half of the radioactivity from oral administration of netupitant [14C] was recovered from urine and feces within 120 hours after administration. The terminal half-life concludes on the 29th-30th day after administration of netupitant.
Palonosetron
After a single oral dose of [14C]-palonosetron 0.75 mg in six healthy volunteers, 85% to 93% of the total radioactivity was excreted in urine, and 5% to 8% was excreted in feces. The amount of unchanged palonosetron in urine is approximately 40% of the administered dose. In healthy volunteers who took 0.5 mg palonosetron capsules, the terminal half-life (t1/2) of palonosetron was 37 ± 12 hours (mean ± standard deviation), and in cancer patients, t1/2 was 48 ± 19 hours. After a single intravenous administration of approximately 0.75 mg palonosetron, the total clearance of palonosetron in healthy volunteers was 160 ± 35 ml/h/kg (mean ± standard deviation), and renal clearance was 66.5 ± 18.2 ml/h/kg.

Pharmacokinetics in Special Patient Groups
Liver Function Impairment
Netupitant
Maximum concentrations and overall exposure to netupitant were increased in patients with mild (n = 8), moderate (n = 8), and severe (n = 2) liver impairment compared to healthy volunteers, although individual variability was recorded in patients with liver impairment and healthy volunteers. The exposure to netupitant (Cmax, AUC 0-t, and AUC 0-?) compared to corresponding healthy volunteers was 11%, 28%, and 19% higher in mild impairment and 70%, 88%, and 143% higher in moderate liver impairment, respectively. Therefore, dose adjustment for patients with mild and moderate liver impairment is not required. There is limited data regarding patients with severe liver impairment (according to Child-Pugh classification ≥9).
Palonosetron
Liver impairment does not significantly affect the overall clearance of palonosetron compared to healthy volunteers. While the terminal half-life and mean systemic exposure of palonosetron increase in patients with severe liver impairment, dose reduction is not required.

Renal Function Impairment
Netupitant
Specific studies to assess the effect of netupitant on patients with renal impairment have not been conducted. In the ADME study, less than 5% of all materials associated with netupitant were eliminated from the body via urine, and less than 1% of the netupitant dose was excreted unchanged in urine, so any accumulation of netupitant or metabolites after a single dose is negligible. Furthermore, population PK studies did not show a correlation between PK parameters of netupitant and markers of renal dysfunction.
Palonosetron
Mild and moderate renal impairment does not significantly affect the PK parameters of palonosetron. The overall systemic exposure of intravenously administered palonosetron in patients with severe renal impairment compared to healthy volunteers increased by approximately 28%. In the population PK study, patients with reduced creatinine clearance (CLCR) also had decreased clearance of palonosetron, but this decrease did not lead to a significant change in the exposure of palonosetron.
Thus, Akynzeo can be administered to patients with renal impairment without dose adjustment.
The effects of netupitant and palonosetron have not been evaluated in patients with end-stage renal failure.