Pharmacy & Therapeutics - October 2008 - (Page PP11)

PRODUCT PROFILER: Granisetron Transdermal Delivery System ation in blood levels and AUC concentration were similar in magnitude to that observed after oral administration of granisetron. This supports the idea that the variability was related to the absorption, metabolism, and excretion of the drug, as opposed to a great variation in the delivery from GTDS.21 As shown in Figure 3, there was no significant drop in plasma levels during the 12-hour period after patch removal.21 All subjects received the patches as specified. Assuming that all drug depleted from the used patches was delivered transdermally, the subjects received between 4.88 and 6.7 mg of granisetron within the 120hour (five-day) application period.21 In 11 subjects, a total of 50 treatment-emergent AEs occurred. Forty-seven of the 50 AEs were related to the drug or patch. All AEs were resolved by the end of the study. Most AEs were mild in nature, some were moderate, and no deaths or serious AEs occurred.21 The only systemic AEs that were recorded as drug-related were headache and constipation, which are expected side effects of oral granisetron.21 Local AEs that occurred in both groups were the sort that would be expected with the application of any transdermal patch (e.g., erythema). In fact, there were slightly more local AEs with the placebo group patch than with the granisetron patch, indicating that topical application of granisetron did not result in additional local AEs.21 Vital signs, 12-lead ECGs, and physical examinations did not show clinically relevant changes during the study or, respectively, at the poststudy examination.21 The placebo patch was applied only to compare local skin tolerability (adhesiveness). In general, adhesiveness of this patch was good, with small patch detachments occurring in fewer than 10% of patients, mainly between hours 14 and 36 and hour 120.21 In summary, this study demonstrated the sustained bioavailability of the granisetron patch, which demonstrated low dermal irritation potential and acceptable adhesiveness. The study patch was safe and well tolerated in all subjects, both systemically and locally. Study 392MD/11/C: A Phase 1 Study Of Bioavailability, Dose, Proportionality, Local Tolerance, Safety, Tolerability, and Adhesion20 A four-way, crossover phase 1 open-label pharmacokinetics trial was conducted to evaluate a single application of three different dosages of one GTDS formulation applied for six days with once-daily dosing of 2-mg granisetron tablets (Kevatril®) to healthy male subjects. This study was conducted in Germany from June to August 2005. The primary objective was to compare the bioavailability of GTDS after a single six-day application to the upper outer arm of three dosages of one GTDS formulation with that of 2 mg once-daily oral granisetron for five days. Secondary objectives were to assess the dose proportionality of granisetron pharmacokinetics after a single GTDS application for six days and to evaluate local tolerance, safety, tolerability, and the adhesion of GTDS.20 Twelve healthy men between 18 and 45 years of age were included in the trial and received the four following treatments according to a randomized, crossover design:20 • treatment A: a once-daily dose of a 2-mg granisetron tablet (Kevatril) for five days • treatment B: GTDS, 52 cm2 6% (34.3 mg), applied for six days on the upper outer arm • treatment C: GTDS, 33 cm2 6% (21.8 mg), applied for six days on the upper outer arm • treatment D: GTDS, 15 cm2 6% (9.9 mg), applied for six days on the upper outer arm The granisetron patch was applied on naive sites alternatively on the left arm, the right arm, and the left upper outer arm. There was a five-day washout period between each treatment.20 As in the previous study, patients were instructed to refrain from taking any other medications.20 Serial blood samples were taken before and up to 240 hours (10 days) after GTDS application (e.g., up to 96 hours [four days] after patch removal) and up to 72 hours (three days) after the last oral dose was given. The investigators assessed plasma concentrations of granisetron using a high-performance liquid chromatography (HPLC)–fluorescence method, with a limit of quantification of 0.1 ng/mL. They assessed local tolerance by a scoring system, clinical examination, and the occurrence of AEs.20 All 12 subjects completed the study and were included in the pharmacokinetic and safety analyses. The pharmacokinetic results (mean [CV%]) for treatment A (oral granisetron) are summarized in Table 2. The steady state of granisetron was reached after the second dosing day, with no accumulation of granisetron observed either on Cmax or Cavg. At steady 11

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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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