MORE ON TRANSDERMAL GL YCERYL TRINITRATE

Good kinetic and dynamic properties The transdermal glyceryl trinitrate therapeutic system allows active drug to diffuse through a semipermeable membrane

at a rate of 40 Jtg/hour/cm2 in vitro. Six healthy volunteers had I, 2 and 4 systems applied to determine dose response.

With all 3 dose levels steady-state plasma levels were reached within 2 hours and no distinct peaks were noted. At

steady-state, the mean plasma levels were 0.16, 0.25 and 0.57ngjml for 1, 2 and 4 systems, respectively. There was a

significant linear relationship between dose and plasma levels. The AUCs for the 3 doses were in the ratio of

I: 1.44: 3.34. lnterindividual variation in plasma levels was small (0.54I-1.510ng/ml with 4 systems). At all 3 dose

levels, passive tilting from a supine position resulted in a lower systolic BP than with placebo and orthostatic heart

rate was increased by 7-IO beats/min. A pilot trial, using 2 subjects who had I transdermal system and 2 subjects with 2 transdermal systems, was designed

to show the effects of daily application of the system over a 4-5 day period. No signs of drug accumulation were

detected and renewal of the systems did not alter plasma levels. The 2 subjects wearing 2 systems experienced severe

headaches, nausea and vomiting on the first day. A crossover tolerability study was therefore conducted in which I2 subjects randomly received active drug or placebo

systems for 10 days. The devices were renewed daily. The average plasma level of glyceryl trinitrate in this study

immediately before renewal of the system, was 0.18 ngjml on day 5 and 0.15 ngjml on day 10. Heart rate was only

minimally above placebo values while on the medication, and orthostatic changes in heart rate were not significantly

altered. During the study no influence by the treatment on ECG tracing or body weight was seen. However, after 5

days of drug treatment, haemoglobin was lower than on placebo (15.8 g/dl vs 16.1 g/dl) and the haematocrit was

slightly reduced (44.7% vs 45.7%). At 10 days this difference was no longer detectable. The main adverse effect

throughout the studies was headache. The incidence and intensity of this diminished as the studies progressed. Local

erythema was also noted but resolved spontaneously. Muller, P. et al.: European Journal of Clinical Pharmacology 22: 473 (No 6, 1982)

14 INPHARMA 16 Oct 1982 0156-2703/82/1016-0014/0$01.00/0 © ADIS Press