Chemical formula: C₁₈H₂₄N₄O Molecular mass: 312.417 g/mol PubChem compound: 5284566
Granisetron is a potent anti-emetic and highly selective antagonist of 5-hydroxytryptamine (5HT3 receptors). Pharmacological studies have demonstrated that granisetron is effective against nausea and vomiting as a result of cytostatic therapy. Radioligand binding studies have demonstrated that granisetron has negligible affinity for other receptor types, including 5HT1, 5HT2, 5HT4 and dopamine D2 binding sites.
Serotonin is the main neurotransmitter responsible for emesis after chemo- or radio-therapy. The 5-HT3 receptors are located in three sites: vagal nerve terminals in the gastrointestinal tract and chemoreceptor trigger zones located in the area postrema and the nucleus tractus solidarius of the vomiting center in the brainstem. The chemoreceptor trigger zones are located at the caudal end of the fourth ventricle (area postrema). This structure lacks an effective blood-brain barrier, and will detect emetic agents in both the systemic circulation and the cerebrospinal fluid. The vomiting centre is located in the brainstem medullary structures. It receives major inputs from the chemoreceptor trigger zones, and a vagal and sympathetic input from the gut.
Following exposure to radiation or cytotoxic substances, serotonin (5-HT) is released from enterochromaffine cells in the small intestinal mucosa, which are adjacent to the vagal afferent neurons on which 5-HT3 receptors are located. The released serotonin activates vagal neurons via the 5-HT3 receptors which lead ultimately to a severe emetic response mediated via the chemoreceptor trigger zone within the area postrema.
Granisetron administered orally has been shown to prevent nausea and vomiting associated with cancer chemotherapy in adults.
Granisetron administered orally has been shown to be effective for prevention and treatment of post-operative nausea and vomiting in adults.
Interaction with neurotropic and other active substances through its activity on P 450-cytochrome has been reported.
In vitro studies have shown that the cytochrome P450 sub-family 3A4 (involved in the metabolism of some of the main narcotic agents) is not modified by granisetron. Although ketoconazole was shown to inhibit the ring oxidation of granisetron in vitro, this action is not considered clinically relevant. Although QT-prolongation has been observed with 5-HT3 receptor antagonists, this effect is of such occurrence and magnitude that it does not bear clinical significance in normal subjects. Nonetheless it is advisable to monitor both ECG and clinical abnormalities when treating patients concurrently with drugs known to prolong the QT.
Pharmacokinetics of the oral administration is linear up to 2.5-fold of the recommended dose in adults. It is clear from the extensive dose-finding programme that the antiemetic efficacy is not unequivocally correlated with either administered doses or plasma concentrations of granisetron.
A fourfold increase in the initial prophylactic dose of granisetron made no difference in terms of either the proportion of patient responding to treatment or in the duration of symptoms control.
Absorption of granisetron is rapid and complete, though oral bioavailability is reduced to about 60% as a result of first pass metabolism. Oral bioavailability is generally not influenced by food.
Granisetron crosses intact skin into the systemic circulation by a passive diffusion process. Following transdermal patch application, granisetron is absorbed slowly, with maximal concentrations reached between 24 and 48 hours.
Based on the measure of residual content of the transdermal patch after removal, approximately 65% of granisetron is delivered resulting in an average daily dose of 3.1 mg per day.
Concurrent administration of a single intravenous bolus of 0.01 mg/kg (maximum 1 mg) granisetron at the same time a granisetron transdermal patch was applied was investigated in healthy subjects. An initial peak in plasma concentrations of granisetron, attributable to the intravenous dose, was reached at 10 minutes post-administration. The known pharmacokinetic profile of the transdermal patch over the period of wear (7 days) was not affected.
Following consecutive application of two granisetron transdermal patches in healthy subjects, each for seven days, granisetron levels were maintained over the study period with evidence of minimal accumulation.
In a study designed to assess the effect of heat on the transdermal delivery of granisetron from granisetron in healthy subjects, a heat pad generating an average temperature of 42°C was applied over the transdermal patch for 4 hours each day over the 5 day period of wear. While application of the heat pad was associated with a minor and transient increase in the transdermal patch flux during the period of heat pad application, no overall increase in granisetron exposure was observed when compared to a control group.
In a pharmacokinetic study in healthy volunteers, where granisetron transdermal patch was applied for a period of 7 days, mean total exposure (AUC0-infinity) was 416 ng h/ml (range 55-1192 ng h/ml), with a between subject variability of 89%. Mean Cmax was 3.9 ng/ml (range 0.7-9.5 ng/ml), with a between subject variability of 77%. This variability is similar to the known high variability in granisetron pharmacokinetics after oral or intravenous administration.
Granisetron is distributed with a mean volume of distribution of approximately 3 l/kg. Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.
No differences in the metabolic profiles of granisetron were observed between the oral and transdermal uses.
Granisetron is mainly metabolised to 7-hydroxygranisetron and 9’N-desmethylgranisetron. In vitro studies using human liver microsomes indicate that CYP1A1 is the major enzyme responsible for the 7-hydroxylation of granisetron, whereas CYP3A4 contributes to 9’desmethylation.
Granisetron is cleared primarily by hepatic metabolism. After intravenous dosing, the mean plasma clearance ranged from 33.4 to 75.7 l/h in healthy subjects and from 14.7 to 33.6 l/h in patients with wide inter-subject variability. The mean plasma half-life in healthy subjects is 4-6 hours and in patients is 9-12 hours.
After transdermal patch application, the apparent granisetron plasma half-life in healthy subjects was prolonged to approximately 36 hours due to the slow absorption rate of granisetron through the skin.
In clinical studies conducted with granisetron transdermal patch, clearance in cancer patients was shown to be approximately half that of healthy subjects.
After intravenous injection, approximately 12% of the dose is excreted unchanged in the urine of healthy subjects in 48 hours. The remainder of the dose is excreted as metabolites, with 49% in the urine and 34% in the faeces.
The effects of gender on the pharmacokinetics of granisetron transdermal patch have not been specifically studied. No consistent gender effects on pharmacokinetics were observed in clinical studies, with a large inter-individual variability reported in both sexes. Population PK modelling has confirmed the absence of a gender effect on the pharmacokinetics of granisetron transdermal patch.
No clinical studies have been performed specifically to investigate the pharmacokinetics of granisetron transdermal patch in patients with renal or hepatic impairment. No clear relationship between renal function (as measured by creatinine clearance) and granisetron clearance was identified in population PK modelling. In patients with renal failure or hepatic impairment, the pharmacokinetics of granisetron were determined following a single 40 μg/kg intravenous dose of granisetron hydrochloride.
In patients with severe renal failure, data indicate that pharmacokinetic parameters after a single intravenous dose are generally similar to those in normal subjects.
No correlation between creatinine clearance and total clearance was observed in cancer patients, indicating no influence of renal impairment on the pharmacokinetics of granisetron.
In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance of an intravenous dose was approximately halved compared to patients without hepatic involvement. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance well above the recommended dose, dose adjustment in patients with functional hepatic impairment is not necessary.
In elderly subjects after single intravenous doses, pharmacokinetic parameters were within the range found for non-elderly subjects.
In a clinical study no differences were seen in the plasma pharmacokinetics of granisetron transdermal patch in male and female elderly subjects (≥65 years) compared with younger subjects (aged 18-45 years inclusive).
In children, after single intravenous doses, pharmacokinetics are similar to those in adults when appropriate parameters (volume of distribution, total plasma clearance) are normalized for body weight.
In a clinical study designed to assess granisetron exposure from transdermal patch in subjects with differing levels of body fat, using BMI as a surrogate measure for body fat, no differences were seen in the plasma pharmacokinetics of the transdermal patch in male and female subjects with a low BMI [<19.5 kg/m² (males), <18.5 kg/m² (females)] and a high BMI (30.0 to 39.9 kg/m² inclusive) compared to a control group (BMI 20.0 to 24.9 kg/m2inclusive).
Preclinical data did not reveal any special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, reproductive toxicity and genotoxicity. Carcinogenicity studies showed no special hazard for humans when used at the recommended dose. However, when administered in higher doses and over a prolonged period of time, the risk of carcinogenicity cannot be ruled out.
A study in cloned human cardiac ion channels has shown that granisetron has the potential to affect cardiac repolarisation via blockade of hERG potassium channels. Granisetron has been shown to block both sodium and potassium channels, which could affect cardiac depolorisation and repolarisation and therefore PR, QRS, and QT intervals. These data help to clarify the mechanisms by which some of the ECG changes (particularly QT and QRS prolongation) associated with this class of substance can occur. However, there is no modification of the cardiac frequency, blood pressure or the ECG trace. If changes do occur, they are generally without clinical significance.
Granisetron transdermal patches did not show any potential for photoirritation or photosensitivity when tested in vivo in guinea-pigs. Granisetron was not phototoxic when tested in vitro in a mouse fibroblast cell line. When tested for potential photogenotoxicity in vitro in a Chinese hamster ovary (CHO) cell line, granisetron increased the percentage of cells with chromosome damage following photoirradiation. Although, the clinical relevance of this finding is not completely clear, patients should be advised to cover the transdermal patch application site if there is a risk of exposure to sunlight throughout the period of wear and for 10 days following its removal.
When tested for skin sensitising potential in guinea pigs, granisetron showed a low potential for irritancy.
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