12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Granisetron is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT1, 5-HT1A, 5-HT1B/C, 5-HT2; for alpha1-, alpha2-, or beta-adrenoreceptors; for dopamine-D2; or for histamine-H1; benzodiazepine; picrotoxin or opioid receptors.

Serotonin receptors of the 5-HT3 type are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HT3 receptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds.

12.2 Pharmacodynamics

The effect of granisetron on QTc prolongation was evaluated in a randomized, single-blind, positive (moxifloxacin 400 mg) - and placebo controlled parallel study in healthy subjects. A total of 120 subjects were administered Sancuso transdermal system (n=60) or intravenous granisetron (10 mcg/kg over 30 seconds; n=60). In a study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo adjusted, baseline corrected QTc based on Fridericia correction method (QTcF) for Sancuso was below 10 ms. This study suggests that Sancuso does not have significant effects on QT prolongation.

No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in studies using granisetron.

The effect on oro-cecal transit time following application of Sancuso has not been studied. Granisetron hydrochloride injection exhibited no effect on oro-cecal transit time in healthy subjects given a single intravenous infusion of 50 mcg/kg or 200 mcg/kg. Single and multiple oral doses of granisetron hydrochloride slowed colonic transit in healthy subjects.

12.3 Pharmacokinetics

Absorption

Granisetron crosses intact skin into the systemic circulation by a passive diffusion process.

Following a 7-day application of Sancuso transdermal system in 24 healthy subjects, high inter- subject variability in systemic exposure was observed. Maximal concentration was reached at approximately 48 hours (range: 24-168 hours) following application. Mean Cmax was 5 ng/mL (CV: 170%) and mean AUC0-168hr was 527 ng-hr/mL (CV: 173%).

Mean Plasma Concentration of Granisetron (mean ± SD)

Based on the measure of residual content of the transdermal system after removal, approximately 66% (SD: ± 10.9) of granisetron is delivered following transdermal system application for 7 days.

Following consecutive application of two Sancuso transdermal systems, each for seven days, granisetron plasma concentrations were maintained over the study period with evidence of minimal accumulation. The mean plasma concentration at 24 hours after the second transdermal system application was 1.5-fold higher due to residual granisetron from the first transdermal system. As the plasma concentration increased after the second transdermal system application, the difference decreased and the mean plasma concentration at 48 hours was 1.3-fold higher after application of the second transdermal system compared to that after application of the first transdermal system.

In a study designed to assess the effect of heat on the transdermal delivery of granisetron from Sancuso in healthy subjects, a heat pad generating an average temperature of 42°C (107.6°F) was applied over the transdermal system for 4 hours each day over the 5 day period of wear. The application of the heat pad was associated with an increase in plasma granisetron concentrations during the period of heat pad application. The elevated plasma concentration declined after removal of the heat pad. Mean Cmax with intermittent heat exposure was 6% higher than without heat. Mean partial AUCs over 6 hours with 4 hour of heat application (AUC0-6, AUC24-30, and AUC48-54) were 4.9, 1.4, and 1.1 fold higher, respectively, with heat pad than without heat pad [see Dosage and Administration (2), Warnings and Precautions (5.4)].

Distribution

Plasma protein binding is approximately 65%. Granisetron distributes freely between plasma and red blood cells.

Elimination

Metabolism

Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HT3 receptor antagonist activity.

Excretion

Clearance is predominantly by hepatic metabolism. Based on a study with 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, 49% in the urine, and 34% in the feces.

Use in Specific Populations

Geriatric Patients

Following application of Sancuso transdermal system in healthy subjects, mean AUC0-z, Cmax, and Cavg were 17%, 15%, and 16% higher, respectively in male and female elderly subjects (≥ 65 years) compared to younger subjects (aged 18-45 years inclusive). These pharmacokinetic parameters were largely overlapped between the two age groups with high variability (CV: >50%).

Following a single 40 mcg/kg intravenous dose of granisetron hydrochloride in elderly subjects (mean age 71 years), lower clearance and longer half-life were observed compared to younger healthy subjects.

Male and Female Patients

There is evidence to suggest that female subjects had higher granisetron concentrations than males following transdermal system application. However, no statistically significant difference in clinical efficacy outcome was observed between males and females.

Racial or Ethnic Groups

The pharmacokinetic profile of granisetron from Sancuso was assessed in healthy Japanese males. Following the application of a single 6-day Sancuso 52 cm2 transdermal system, in healthy male Japanese subjects, mean Cmax, AUC(0-144), and AUC(0-∞) values were 5.02 ng/mL (CV: 66%), 492 ng.hr/mL (CV: 72%), and 562 ng.hr/mL (CV: 60%), respectively, and a median tmax value was 48 hours.

Patients with Renal Impairment

Total clearance of granisetron was not affected in patients with severe renal failure who received a single 40 mcg/kg intravenous dose of granisetron hydrochloride.

Patients with Hepatic Impairment

In patients with hepatic impairment due to neoplastic liver involvement, total plasma clearance following a single 40 mcg/kg intravenous dose of granisetron hydrochloride was approximately halved compared to patients without hepatic impairment. Given the wide variability in pharmacokinetic parameters of granisetron and the good tolerance of doses well above the recommended dose, dose adjustment in patients with hepatic functional impairment is not necessary.

Body Mass Index

In a clinical study designed to assess granisetron exposure from Sancuso in subjects with differing levels of body fat, using body mass index (BMI) as a surrogate measure for subcutaneous fat, no significant differences were seen in the plasma pharmacokinetics of Sancuso in male and female subjects with low BMI [<19.5 kg/m2 (males), <18.5 kg/m2 (females)] and high BMI (30.0 to 39.9 kg/m2 inclusive) compared to a control group (BMI 20.0 to 24.9 kg/m2 inclusive).

Drug Interaction Studies

Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and hence, the half-life of granisetron. In addition, the activity of the cytochrome P-450 subfamily 3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known. In a human pharmacokinetic study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma clearance of intravenous granisetron hydrochloride. The clinical significance of this change is not known.