PHARMACOKINETICS AND PHARMACODYNAMICS OF A NEW TRANSDERMAL CLONIDINE,M-5041T, IN HEALTHY-SUBJECTS

The pharmacokinetic as well as the pharmacodynamic properties of a new transdermal clonidine, M-5041T (M), and its safety were evaluated aft er 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 eigh t healthy subjects. In the repeated-application study, first (0-72 hou rs), second (72-144 hours), and third (144-216 hours) patches of M 6 m g were applied in seven healthy subjects. In the single-application st udy, plasma clonidine concentration increased in a dose-dependent mann er after application of M. Maximum plasma concentration (Cmax) and are a 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 c learance did not differ significantly among three trials. Blood pressu re (BP) decreased gradually after application of each dose of M. The B P-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 No subject had to be withdrawn from the study because of the appearance of adverse effects.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, pla sma concentration of clonidine increased up to 48 hours after applicat ion of first patch, and thereafter remained within a relatively narrow range until removal of third patch. The Cmax and AUC did not differ s ignificantly among three trials. Blood pressure during an active perio d decreased significantly during treatment with M, whereas BP at midni ght did not change significantly. Two subjects complained of orthostat ic vertigo caused by hypotension and were dropped out of the study. Mi ld erythema and systemic adverse effects were reported. These results suggest that M is a promising tool for the treatment of hypertension w ithout unacceptable skin reactions. Orthostatic change in BP should be monitored carefully during treatment with M.