Population pharmacokinetic modelling of BIBN 4096 BS, the first compound of the new class of calcitonin gene-related peptide receptor antagonists.

Pharmacokinetics (PK) of the calcitonin gene-related (CGRP) peptide receptor antagonist BIBN 4096 BS, the first compound of this new class tested in humans, has been evaluated combining the data from a phase I study performed in healthy volunteers and a phase IIa study conducted in migraine patients. A total of 94 individuals with a total of 556 plasma samples contributed to the analysis. Subjects received a single dose of 0.25, 0.5, 1, 2.5, 5 or 10 mg BIBN 4096 BS administered in a 10 min i.v. infusion. Blood samples were obtained at selected times up to 12 h. Disposition of BIBN 4096 BS was best described with a three compartment body model with first order elimination. BIBN 4096 BS showed a moderate degree (between 30 and 50%) of inter-subject variability in the apparent volume of distribution of the central compartment (V1), total plasma clearance (CL), distribution clearance between the central and deep compartment, and the apparent volume of distribution of the shallow compartment. Typical estimates of V1 were significantly (P <0.01) lower in healthy volunteers (7.16 versus 9.95 L), and typical estimates of CL were significantly lower in subjects receiving oral contraceptives (11.4 versus 17.1 L/h), although the absolute reduction in the unexplained inter-subject variability was negligible (4%). Computer simulations showed that the above mentioned covariates lack clinical significance. In conclusion, the pharmacokinetics of BIBN 4096 BS was independent of the dose and not altered by the tested covariates to a clinically significant degree.

RCT Entities:   Population Interventions Outcomes