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Pharmacology: Pharmacodynamics: Palonosetron is a selective high-affinity receptor antagonist of the 5HT3 receptor.
In two randomised, double-blind studies with a total of 1,132 patients receiving moderately emetogenic chemotherapy that included cisplatin ≤50 mg/m2, carboplatin, cyclophosphamide ≤1,500 mg/m2 and doxorubicin >25 mg/m2, palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg (half-life 4 hours) or dolasetron 100 mg (half-life 7.3 hours) administered intravenously on Day 1, without dexamethasone.
In a randomised, double-blind study with a total of 667 patients receiving highly emetogenic chemotherapy that included cisplatin ≥ 60 mg/m2, cyclophosphamide > 1,500 mg/m2 and dacarbazine, palonosetron 250 micrograms and 750 micrograms were compared with ondansetron 32 mg administered intravenously on Day 1. Dexamethasone was administered prophylactically before chemotherapy in 67 % of patients.
The pivotal studies were not designed to assess efficacy of palonosetron in delayed onset nausea and vomiting. The antiemetic activity was observed during 0-24 hours, 24-120 hours and 0-120 hours. Results for the studies on moderately emetogenic chemotherapy and for the study on highly emetogenic chemotherapy are summarised in the following tables.
Palonosetron was non-inferior versus the comparators in the acute phase of emesis both in moderately and highly emetogenic setting.
Although comparative efficacy of palonosetron in multiple cycles has not been demonstrated in controlled clinical studies, 875 patients enrolled in the three phase 3 trials continued in an open label safety study and were treated with palonosetron 750 micrograms for up to 9 additional cycles of chemotherapy. The overall safety was maintained during all cycles. (See Tables 1, 2 and 3.)
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Click on icon to see table/diagram/imageThe effect of palonosetron on blood pressure, heart rate, and ECG parameters including QTc were comparable to ondansetron and dolasetron in CINV clinical studies. In non-clinical studies palonosetron possesses the ability to block ion channels involved in ventricular de- and re-polarisation and to prolong action potential duration.
The effect of palonosetron on QTc interval was evaluated in a double blind, randomised, parallel, placebo and positive (moxifloxacin) controlled trial in adult men and women. The objective was to evaluate the ECG effects of IV administered palonosetron at single doses of 0.25, 0.75 or 2.25 mg in 221 healthy subjects. The study demonstrated no effect on QT/QTc interval duration as well as any other ECG interval at doses up to 2.25 mg. No clinically significant changes were shown on heart rate, atrioventricular (AV) conduction and cardiac repolarisation.
Paediatric population: Prevention of Chemotherapy Induced Nausea and Vomiting (CINV): The safety and efficacy of Palonosetron i.v at single doses of 3μg/kg and 10μg/kg was investigated in a clinical study in 72 patients in the following age groups, >28 days to 23 months (12 patients), 2 to 11 years (31 patients), and 12 to 17 years of age (29 patients), receiving highly or moderately emetogenic chemotherapy. No safety concerns were raised at either dose level. The primary efficacy variable was the proportion of patients with a complete response (CR, defined as no emetic episode and no rescue medication) during the first 24 hours after the start of chemotherapy administration. Efficacy after palonosetron 10 μg/kg compared to palonosetron 3μg/kg was 54.1% and 37.1% respectively. Refer to Pharmacokinetics as follows.
Prevention of Post Operative Nausea and Vomiting (PONV): The safety and efficacy of Palonosetron i.v. at single doses of 1μg/kg and 3μg/kg was compared in a clinical study in 150 patients in the following age groups, >28 days to 23 months (7 patients), 2 to 11 years (96 patients), and 12 to 16 years of age (47 patients) undergoing elective surgery. No safety concerns were raised in either treatment group. The proportion of patients without emesis during 0-72 hours post-operatively was similar after palonosetron 1 μg/kg or 3 μg/kg (88% vs 84%).
Refer to the information on paediatric use.
Pharmacokinetics: Absorption: Following intravenous administration, an initial decline in plasma concentrations is followed by slow elimination from the body with a mean terminal elimination half-life of approximately 40 hours. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-∞) are generally dose-proportional over the dose range of 0.3-90 μg/kg in healthy subjects and in cancer patients.
Following intravenous administration of palonosetron 0.25 mg once every other day for 3 doses in 11 testicular cancer patients, the mean (± SD) increase in plasma concentration from Day 1 to Day 5 was 42 ± 34 %. After intravenous administration of palonosetron 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 %.
Pharmacokinetic simulations indicate that the overall exposure (AUC0-∞) of 0.25 mg intravenous palonosetron administered once daily for 3 consecutive days was similar to a single intravenous dose of 0.75 mg, although Cmax of the 0.75 mg single dose was higher.
Distribution: Palonosetron at the recommended dose is widely distributed in the body with a volume of distribution of approximately 6.9 to 7.9 l/kg. Approximately 62 % of palonosetron is bound to plasma proteins.
Biotransformation: Palonosetron is eliminated by dual route, about 40 % eliminated through the kidney and with approximately 50 % metabolised to form two primary metabolites, which have less than 1 % of the 5HT3 receptor antagonist activity of palonosetron. In vitro metabolism studies have shown that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 isoenzymes are involved in the metabolism of palonosetron. However, clinical pharmacokinetic parameters are not significantly different between poor and extensive metabolisers of CYP2D6 substrates. Palonosetron does not inhibit or induce cytochrome P450 isoenzymes at clinically relevant concentrations.
Elimination: After a single intravenous dose of 10 micrograms/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, as unchanged active substance. After a single intravenous bolus administration in healthy subjects the total body clearance of palonosetron was 173 ± 73 ml/min and renal clearance was 53 ± 29 ml/min. The low total body clearance and large volume of distribution resulted in a terminal elimination half-life in plasma of approximately 40 hours. Ten percent of patients have a mean terminal elimination half-life greater than 100 hours.
Pharmacokinetics in special populations: Elderly: Age does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary in elderly patients.
Gender: Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary based on gender.
Paediatric population: Across all age groups, (>28 days to 23 months (11 patients), 2 to 11 years (30 patients), and 12 to 17 years of age (29 patients)) of CINV paediatric patients, exposure to palonosetron was generally dose proportional for the 3μg/kg and 10μg/kg dose levels. Both clearance and volume of distribution appear to increase with increasing age largely due to the expected increase in body weight among the age groups. Mean terminal elimination half life values ranged from 21-37 hours and did not change with dose or age. There was no effect of gender on clearance, volume of distribution or half-life. Refer to information on paediatric use.
Renal impairment: Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Severe renal impairment reduces renal clearance, however total body clearance in these patients is similar to healthy subjects. No dosage adjustment is necessary in patients with renal insufficiency. No pharmacokinetic data in haemodialysis patients are available.
Hepatic impairment: 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.
Toxicology: Preclinical safety data: 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.
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.
Palonosetron is not mutagenic. High doses of palonosetron (each dose causing at least 30 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 Palonosetron Hydrochloride is intended for single application in humans, these findings are not considered relevant for clinical use.
