TOLERABILITY, SAFETY AND PHARMACOKINETICS OF SINGLE-DOSE AND MULTIPLEDOSING OF THE SELECTIVE D1 ANTAGONIST NNC-01-0687 IN HEALTHY-SUBJECTS

Selective dopamine D-1-receptor antagonists have been shown to exhibit similar effects in animal models for antipsychotic action as the sele ctive D-2 antagonists. NNC 01-0687, a benzazepine with selective and h igh affinity to the D-1-receptor, was well tolerated by healthy subjec ts allocated to double blind, placebo controlled studies. Complaints o f moderate restlessness and drowsiness were reported after administrat ion of 25 mg NNC 01-0687, indicating the dose to be the maximum tolera ted single dose. The highest multiple dose level of a daily dose of 45 mg NNC 01-0687 administered t.i.d. for 14 days was assessed as safe a nd well-tolerated with few reports of adverse events. Some alanine ami notransferase (ALT) elevations appeared in both treatment groups (acti ve and placebo) and no evident influence of NNC 01-0687 on the liver f unction could be derived. No statistically significant or clinically r elevant effects were observed in haematological parameters, urinalyses , blood pressure, heart rate, ECG or plasma levels of prolactin, corti sol or growth hormone. The plasma drug concentration curves indicated a fast absorption with t(max) at 0.5-1 h and an apparent elimination h alf-life of 3-4 h. Both AUC and C-max appeared to be linearly correlat ed to the dose, indicating linear pharmacokinetics. With similar C-max and AUC on day 1 and day 10 no accumulation was observed. When admini stered just after lunch, the C-max was reduced by 50-60% and the t(max ) increased to 3 h, but without change of AUC.