BIBN 4096 BS ([R-(R*,S*)]-N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-,1-piperidinecarboxamide) is the first selective, highly potent, small molecule, nonpeptide calcitonin gene-related peptide (CGRP) receptor antagonist, which has been developed for the treatment of acute migraine. The objective of this study was to obtain information on the safety, tolerability and pharmacokinetics of BIBN 4096 BS following single intravenous administration of rising doses (0.1, 0.25, 0.5, 1, 2.5, 5 and 10 mg) in 55 healthy male and female volunteers. The study was of single-centre, double-blind (within dose levels), placebo-controlled, randomized, single rising dose design. Blood pressure, pulse rate, respiratory rate, ECG, laboratory tests and forearm blood flow did not reveal any clinically relevant, drug-induced changes. Sixteen adverse events (AEs) were reported by eight of 41 volunteers after BIBN 4096 BS compared to five AEs reported by four of 14 volunteers after placebo. Approximately two-thirds of all AEs related to active treatment occurred at the highest dose of 10 mg. At this dose level, all AEs were confined to the three BIBN 4096 BS-treated females, and consisted mainly of transient and mild paresthesias. Paresthesias were the single most frequent AE, whereas fatigue was the AE which occurred in the highest number of subjects. Only two AEs were of moderate intensity, all remaining AEs were of mild intensity. No serious AEs were reported. The local tolerability after intravenous administration was good. In summary, intravenously administered BIBN 4096 BS revealed a very favourable safety profile over the dose range tested in both genders. Generally well tolerated at all dose levels, it was of satisfactory tolerability in female subjects at the highest dose of 10 mg. The plasma concentration-time courses of BIBN 4096 BS showed multicompartmental disposition characteristics. Mean maximum concentration (Cmax) values appeared to be dose-proportional. Based on the results from the two high dose levels (5 and 10 mg) with sufficient individual subject data, BIBN 4096 BS exhibited a total plasma clearance (CL) of approximately 12 l/h and an apparent volume of distribution at steady state (Vss) of approximately 20 l, resulting in a terminal half-life (t1/2) of approximately 2.5 h. Inter-individual variability was moderate with a coefficient of variation of approximately 45% based on the area under the plasma concentration-time curve (AUC) values. The mean renal clearance (CLR) was approximately 2 l/h, suggesting that renal excretion plays only a minor role in the elimination of unchanged BIBN 4096 BS.

AimsThe aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)‐2C19.MethodsThe present randomized, double‐blind, placebo‐controlled, single‐centre study evaluated single rising doses of BI 409306 (0.5–500 mg) administered as a tablet or oral solution to EMs or PMs.ResultsOf 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20–30 min) after administration and mostly resolved within 1–2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (Cmax) was reached <1 h after drug administration, and the half‐life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, Cmax was 2.2–2.3‐fold higher, and the area under the plasma concentration–time curve over the time interval 0 extrapolated to infinity was 4.1–5.0‐fold higher compared with EMs.ConclusionsIn healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level.

The tolerability and hemodynamic and humoral effects of the structurally novel calcium antagonist Ro 40-5967 were investigated in 64 patients with hypertension. In a double-blind, placebo-controlled study, ascending oral doses of 50, 100, 150, or 200 mg were administered once daily for 8 days in a solution. Ro 40-5967 was well tolerated up to 150 mg, but treatment was stopped in one patient in the 200 mg group because of bradycardia. Blood pressure was dose-dependently reduced over the full 24-hour dosing period with more pronounced effects on day 8 than on day 1. The maximum blood pressure reduction was obtained after 150 mg (supine blood pressure, -34/-25 mm Hg, p less than 0.001). Despite a slight decrease in supine heart rate, cardiac output increased. PQ time was dose-dependently increased and concentration-effect analysis showed that relevant atrioventricular conduction disturbances occur only at concentrations much higher than those required to reduce blood pressure. Changes in catecholamines, plasma renin activity, and aldosterone were small and inconsistent. In conclusion, Ro 40-5967 has a long-lasting antihypertensive effect after once-daily administration.