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.