Pharmacy & Therapeutics - October 2008 - (Page PP9)

PRODUCT PROFILER: Granisetron Transdermal Delivery System Chemistry and Pharmacokinetics CHEMICAL AND PHYSICAL PROPERTIES16 Granisetron HCl is an antinauseant and antiemetic agent. It is chemically designated as endo-N-(9-methyl9-azabicyclo [3.3.1] non-3-yl)-1-methyl-1H-indazole-3carboxamide HCl. Its molecular weight is 348.9 (312.4 free base), and its empirical formula is C18H24N4O·HCl (Figure 2). containing 21.8 mg of granisetron, and a 52-cm2 containing 34.3 mg of granisetron, applied for six days with 2 mg of oral granisetron. After the patches were applied for six days, granisetron was slowly absorbed, with maximal concentrations reached 48 hours after patch application and with mean values of 0.99, 1.74, and 3.39 ng/mL, for the 15-cm2, 33-cm2, and 52-cm2 patches, respectively. The mean concentration (Cavg) of granisetron was 0.68, 1.24, and 2.23 ng/mL for 15 cm2, 33 cm2, and 52 cm2, respectively. Granisetron’s pharmacokinetic parameters were proportional to patch size, with the 52-cm2 patch resulting in Cavg concentrations similar to those for once-daily oral dosing of granisetron 2 mg. The in vivo delivery rate for this patch was 3.30 mg/day.20 Further details are presented in the Clinical Trials discussion beginning on page 10. Distribution16 Plasma protein binding is approximately 65%, and granisetron is distributed freely between plasma and red blood cells. Metabolism and Excretion16 Metabolism of granisetron involves N-demethylation and aromatic ring oxidation, followed by conjugation. In vitro liver chromosomal studies show that granisetron’s major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P450 3A subfamily. Animal studies indicate that some of the metabolites may also have 5-HT3 receptor antagonist activity.16 Clearance is predominantly hepatic.16 MECHANISM OF ACTION AND CLINICAL PHARMACOLOGY16 Granisetron is a selective 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.16 The 5-HT3 receptors are located peripherally on vagal nerve terminals and centrally in the chemo receptor trigger zone (CTZ) of the area postrema. When a patient has CINV, 5HT3 receptors are stimulated by serotonin, which is released from the mucosal enterochromaffin cells. In binding to 5-HT3 receptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli.16 PHARMACOKINETICS AND DRUG METABOLISM Absorption A phase 1, four-way, crossover, open-label pharmacokinetics study of single application of three different dosages of one GTDS formulation was conducted in healthy subjects. The formulations included a 15-cm2 patch containing 9.9 mg of granisetron, a 33-cm2 patch O NH N N CH3 N CH3 · HCl Figure 2 Chemical structure of granisetron HCl. (From Kytril® prescribing information.16) 9

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Pharmacy & Therapeutics - October 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Medical Management of Parkinson’s Disease Why Is Health Care Regulation So Complex? The Next President’s Prescription for Action on Drugs Trends in Managing Multiple Sclerosis Product Profiler: Sancuso®

Pharmacy & Therapeutics - October 2008

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