Source: Health Products Regulatory Authority (ZA) Revision Year: 2012 Publisher: Pfizer Laboratories (Pty) Ltd, 85 Bute Lane, Sandton, 2196
A. 5.10 Serotonin antagonists
Palonosetron is a potent and selective serotonin subtype 3 (5-HT3) receptor antagonist with a strong binding affinity for this receptor – both in vitro and in vivo. Palonosetron has little or no affinity for other bioreceptors, including other serotonergic receptors (5-HT1, 5-HT2 and 5-HT4).
The major human metabolites, M9 and M4, have only marginal clinically non-relevant activity.
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 2 days [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.
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.
Palonosetron is eliminated by dual route, about 40% eliminated through the kidney and with approximately 50% metabolised to form two primary metabolites, M9 and M4, which have less than 1% of the 5-HT3 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. Palonosteron does not inhibit or induce cytochrome P450 isoenzymes at clinically relevant concentrations.
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 ± 73ml/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.
Age does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary in elderly patients.
Gender does not affect the pharmacokinetics of palonosetron. No dosage adjustment is necessary based on gender.
No pharmacokinetic data are available in patients below 18 years of age.
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 does not significantly affect total body clearance of palonosetron compared to 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.
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