PMID- 15265053
OWN - NLM
STAT- MEDLINE
DCOM- 20040930
LR  - 20210112
IS  - 0333-1024 (Print)
IS  - 0333-1024 (Linking)
VI  - 24
IP  - 8
DP  - 2004 Aug
TI  - Safety, tolerability and pharmacokinetics of BIBN 4096 BS, the first selective 
      small molecule calcitonin gene-related peptide receptor antagonist, following 
      single intravenous administration in healthy volunteers.
PG  - 645-56
AB  - 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.
FAU - Iovino, M
AU  - Iovino M
AD  - Human Pharmacology Centre, Department of Clinical Research, Boehringer Ingleheim 
      Pharma GmbH & Co. KG, Ingelheim, Germany. 
      Mario.Iovino@ing.boehringer-ingelheim.com
FAU - Feifel, U
AU  - Feifel U
FAU - Yong, C-L
AU  - Yong CL
FAU - Wolters, J-M
AU  - Wolters JM
FAU - Wallenstein, G
AU  - Wallenstein G
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - England
TA  - Cephalalgia
JT  - Cephalalgia : an international journal of headache
JID - 8200710
RN  - 0 (Calcitonin Gene-Related Peptide Receptor Antagonists)
RN  - 0 (Piperazines)
RN  - 0 (Quinazolines)
RN  - WOA5J8TX6M (olcegepant)
SB  - IM
MH  - Adult
MH  - Area Under Curve
MH  - *Calcitonin Gene-Related Peptide Receptor Antagonists
MH  - Cardiovascular Physiological Phenomena/drug effects
MH  - Female
MH  - Half-Life
MH  - Humans
MH  - Infusions, Intravenous
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - Piperazines/*administration & dosage/*adverse effects/*pharmacokinetics
MH  - Quinazolines/*administration & dosage/*adverse effects/*pharmacokinetics
EDAT- 2004/07/22 05:00
MHDA- 2004/10/01 05:00
CRDT- 2004/07/22 05:00
PHST- 2004/07/22 05:00 [pubmed]
PHST- 2004/10/01 05:00 [medline]
PHST- 2004/07/22 05:00 [entrez]
AID - CHA726 [pii]
AID - 10.1111/j.1468-2982.2004.00726.x [doi]
PST - ppublish
SO  - Cephalalgia. 2004 Aug;24(8):645-56. doi: 10.1111/j.1468-2982.2004.00726.x.