Pharmacy & Therapeutics - October 2008 - (Page PP12)

PRODUCT PROFILER: Granisetron Transdermal Delivery System Table 2 Plasma Pharmacokinetics of Granisetron Tablets (Kevatril®) 2 mg (Daily Oral Dosing for Five Days); Mean (CV%) Day 1 (N = 12 Patients) Cmax tmax AUC (0–24 hour) Cavg AUC (0–∞) t1⁄2 Rac, obs Rac, pred (ng/mL) (hr)a (ng • hr/mL) (ng/mL) (ng • hr/mL) (h) c c 5.25 (42) 1.5 [1–4] 51(80) 2.14 (80) 65 (96) 6.4 (74) 0.88 (58) 1.170 (21) Day 5 (N = 12 Patients) 5.5 2.0 62.0 2.60 98 7.9 (68) [1–4] (110) (110) (120) b (74) b ANOVA (Day Effect) P = 0.5111 P = 0.9509 — P = 0.5722 P = 0.8146 P = 0.0635 — — a, median (min–max); b, N = 11; c, geometric mean. ANOVA = analysis of variance; AUC = area-under-the-curve concentration; Cavg = average concentration; Cmax = peak concentration; CV = coefficient of variation; hr = hour; hr = hour; Rac, obs = observed accumulation ratio; Rac, pred = predicted accumulation ratio; tmax = time to peak concentration; t1/2 = half-life. From Study 392MD/11/C, p 33.20 state, average Cavg and mean Cmax of granisetron were 2.60 and 5.5 ng/mL, respectively. Between-subject variability was high, with a CV of 42% to 68% for Cmax and a CV of 80% to 120% for the AUC concentration. Pharmacokinetic parameters for granisetron (mean [CV%)]) for treatments B, C, and D (GTDS) for six days are summarized in Table 3 and Figure 4. In this study, the mean Cavg, AUC concentration, and in vivo flux increased proportionally with the granisetron patch size. The terminal elimination half-life was similar for all three arms, with an overall mean of approximately 36 hours. Patch size did not affect the magnitude of variation of minimal and maximal granisetron concentrations of Cavg, as shown by similar relative fluctuation (Rf).20 Between-subject variability of the granisetron pharmacokinetics after patch application was high, with a CV of 83% to 110% for Cavg. Skin tolerability was acceptable for the three doses of the transdermal system. Patch adhesiveness was good, and nearly all applied patches adhered properly; only two of the 36 patches had become completely unstuck.20 For all treatments, the mean irritation score was highest one hour after patch removal. Table 4 presents the scoring system. Mean irritation score values were 0.6 for treatment B (52 cm2), 1.0 for treatment C (33 cm2), and 0.7 for treatment D (15 cm2). These increases were likely a result of mechanical irritation after patch removal. Within 96 hours (on Day 11 at the end of observation), these values decreased spontaneously to 0 with treatment B, to 0.3 with treatment C, and to 0 with treatment D.20 The maximal irritation score Table 3 Plasma Pharmacokinetics of Granisetron after Application of the Granisetron Transdermal Patch for Six Days; Mean (CV%) Granisetron TDS Treatment D: 15 cm2 (N = 12 Patients) Cavg Cavg/dose AUC (0–∞) AUC (0–∞)/dose t1⁄2 In vivo flux In vivo flux/dose Rf (ng/mL) (ng • hr/mL) (hr) (mg/24 hr) 0.68 0.045 149 9.9 30.9 1.02 0.068 1.12 (83) (83) (70) a (70) a (32) a (86) (86) (48) Treatment C: 33 cm2 (N = 10 Patients) 1.24 0.038 287 8.7 30.9 1.90 0.057 1.13 (110) (110) (95) b (95) b (21) b (110) (110) (70) Treatment B: 52 cm2 (N = 12 Patients) 2.23 0.043 420 8.1 35.9 3.30 0.063 1.20 (89) (89) (89) (89) (35) (93) (93) (69) ANOVA (Patch Size Effect) — P = 0.1542 — P = 0.0514 P = 0.3232 — P = 0.1554 P = 0.9256 a, n =10; b, n = 8. ANOVA = analysis of variance; AUC = area under-the-curve concentration; Cavg = average peak concentration; CV = coefficient of variation; hr = hour; Rf = relative fluctuation; t1/2 = half-life. From Study 392MD/11/C, p 34.20 12

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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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