title: Modelling the anti-migraine effects of BIBN 4096 BS: a new calcitonin gene-related peptide receptor antagonist.
abstract: OBJECTIVE
  Migraine attacks are associated with release of the calcitonin gene-related peptide (CGRP) from trigeminal nerves. BIBN 4096 BS is the first CGRP receptor antagonist tested in humans showing response rates similar to those reported for triptans, together with very good safety and tolerability profiles. The objective of the current study is to develop a population pharmacokinetic/pharmacodynamic model resembling the mechanism of action of BIBN 4096 BS, and to extract by model-based simulations dosage formulations and pharmacodynamic properties that can assist in the development of CGRP receptor antagonists.
  
  
  METHODS
  126 patients with an acute moderate to severe migraine attack lasting not more than 6 hours were enrolled in this phase IIa study. BIBN 4096 BS was given as a single intravenous 10-minute infusion at different dose levels ranging from 0.25 to 10 mg. Severity of headache was measured up to 24 hours. Patients who did not show pain relief by 2 hours were allowed to take rescue medication. Severity of headache and time to rescue medication measurements were fitted simultaneously using logistic regression and time-to-event analysis with nonlinear mixed-effect modelling software NONMEM version V.
  
  
  RESULTS
  Severity of headache and time to rescue medication were described as a function of the fraction of the CGRP receptors blocked by BIBN 4096 BS, and controlled by the second- and first-order rate constants representing the onset (k(on)) and offset (k(off)) of the anti-migraine effects. The model predicted a slow rate of offset of the anti-migraine effect (half-life of k(off) = 21 hours). The model developed described the data well and was validated properly.
  
  
  CONCLUSIONS
  A semi-mechanistic population pharmacokinetic/pharmacodynamic model has been developed for the anti-migraine effects of BIBN 4096 BS, characterised by the severity of headache and time to rescue medication. Simulations exploring the effect of the rate of absorption, bioavailability after an extravascular administration and the rate of activation/inactivation of the anti-migraine effect were performed. The rate of absorption seems to play a minor role; however, at least bioavailability fractions of 0.2-0.3 should be obtained. With regard to the kinetics of the anti-migraine effect, and to achieve a response rate of 60% at 2 hours, values of k(on) should be > 0.081 mL/ng/h. At later times after administration higher values of k(off) are associated with faster offset of the response. The simulations showed that molecules with high k(on) and low k(off) values are the most promising.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, Spain.
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
authors.forename: Jan-Markus
authors.initials: JM
authors.lastname: Wolters
authors.forename: Christiane
authors.initials: C
authors.lastname: Tillmann
authors.forename: Hans G
authors.initials: HG
authors.lastname: Schaefer
authors.forename: Willy
authors.initials: W
authors.lastname: Roth
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D001682:Biological Availability; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004151:Dipeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy* / Q000378:metabolism; D015233:Models, Statistical; D017711:Nonlinear Dynamics; D011153:Population; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011955:Receptors, Drug / Q000187:drug effects; D012984:Software
chemical_list: C505165:1-(N(2)-(3,4-dibromo-N-((4-(3,4-dihydro-2(1H)-oxoquinazolin-3-yl)-1-piperidinyl)carbonyl)tyrosyl)lysyl)-4-(4-pyridinyl)piperazine; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004151:Dipeptides; D011799:Quinazolines; D011955:Receptors, Drug