Pharmacokinetics and Pharmacodynamics of a New Transdermal Clonidine, M‐5041T, in Healthy Subjects

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Abstract
The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M‐5041T (M), and its safety were evaluated after single and repeated applications. In the single‐application study, one patch of M (4 mg → 6 mg → 8 mg) was applied for 3 days in eight healthy subjects. In the repeated‐application study, first (0–72 hours), second (72–144 hours), and third (144–216 hours) patches of M 6 mg were applied in seven healthy subjects. In the single‐application study, plasma clonidine concentration increased in a dose‐dependent manner after application of M. Maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) increased in a dose‐dependent manner, but the difference did not reach significance. Time to maximum concentration, elimination half‐life, and total and renal clearance did not differ significantly among three trials. Blood pressure (BP) decreased gradually after application of each dose of M. The BP‐lowering effect of M 8 mg was greater than that of M 4 mg and 6 mg. Adverse effects such as erythema and drowsiness were reported in some subjects. No subject had to be withdrawn from the study because of the appearance of adverse effects. In the repeated‐application study, plasma concentration of clonidine increased up to 48 hours after application of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ significantly among three trials. Blood pressure during an active period decreased significantly during treatment with M, whereas BP at midnight did not change significantly. Two subjects complained of orthostatic vertigo caused by hypotension and were dropped out of the study. Mild erythema and systemic adverse effects were reported. These results suggest that M is a promising tool for the treatment of hypertension without unacceptable skin reactions. Orthostatic change in BP should be monitored carefully during treatment with M.