Modelling the anti-migraine effects of BIBN 4096 BS: a new calcitonin gene-related peptide receptor antagonist.

BACKGROUND AND 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. DISCUSSION: 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.

Population Pharmacokinetic Data Analysis of Cilobradine, an I f Channel Blocker.

PURPOSE: To evaluate the population pharmacokinetic characteristics of cilobradine including a covariate analysis based on six phase I trials and to assess the predictive performance of the model developed. METHODS: Single or multiple doses of cilobradine were administered as solution, capsule or infusion. Two thousand, seven hundred and thirty-three plasma samples (development data set) were used for model development in NONMEM. Model evaluation was performed using also an external data set. RESULTS: Data were best described by a linear three-compartment model. Typical V ss was large ( approximately 100 l) and CL was 21.5 l/h. Covariate analysis revealed a statistically significant but clinically irrelevant relation between KA and dose. Inter-individual variability was moderate (15-46%); imprecision of estimates was generally low. The final model was successfully applied to the external data set revealing its robustness and general applicability. Its final estimates resembled those of the development data set except for the covariate relation not being supported. When excluding the covariate relation, all observations were well predicted. CONCLUSION: A robust population PK model has been developed for cilobradine predicting plasma concentrations from a different study design well. Therefore, the model can serve as a tool to simulate and evaluate different dosing regimens for further clinical trials.

Quinidine does not affect the renal clearance of moxonidine.

AIMS: To test the hypothesis that the renal clearance of moxonidine decreases when dosed with quinidine. METHODS: A randomized, two-period study was conducted with six healthy, male subjects orally dosed with either 0.2 mg moxonidine alone or 1 h after 400 mg quinidine sulphate. Pharmacokinetic parameters were calculated using a noncompartmental analysis method. RESULTS: When coadministered, quinidine significantly increased moxonidine AUC and t1/2 by 11% and 15%, respectively, and decreased CL/F by 10% compared with the control dosing. CLR and Aeur were not significantly different. Clinically, both treatments were well tolerated. CONCLUSIONS: Quinidine does not affect the renal clearance of moxonidine. The decrease in apparent total clearance of moxonidine with quinidine coadministration was possibly due to metabolic inhibition, though not likely to be clinically significant.