RT Journal Article
SR Electronic
T1 A semi-physiological population model for prediction of the pharmacokinetics of drugs under liver and renal disease conditions
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.110.037838
DO 10.1124/dmd.110.037838
A1 Ashley Strougo
A1 Ashraf Yassen
A1 Walter Krauwinkel
A1 Meindert Danhof
A1 Jan Freijer
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/04/12/dmd.110.037838.abstract
AB The application of model-based drug development in special populations becomes increasingly important for clinical trial optimization, mostly by providing rationale for dose selection and thereby aiding risk-benefit assessment. In this paper, a semi-physiological approach is presented enabling the extrapolation of the pharmacokinetics from healthy subjects to patients with different disease conditions. This semi-physiological approach was applied to solifenacin, using clinical data on total and free plasma and urine concentrations in healthy subjects. The analysis was performed using non-linear mixed effect modeling and relied on the utilization of a general partitioning framework to account for binding to plasma-proteins and to non-plasma tissues together with principles from physiology that apply to the main pharmacokinetic process, i.e., bioavailability, distribution and elimination. These physiology principles applied allowed quantification of the impact of key physiological parameters (i.e., body composition, glomerular function, liver enzyme capacity and liver blood flow) on the pharmacokinetics of solifenacin. The prediction of the time course of the drug concentration in liver and renal impaired patients only required adjustment of the physiological parameters that are known to change upon liver and renal dysfunction without modifying the pharmacokinetic model structure and/or its respective parameter estimates. Visual predictive checks showed that the applied approach was able to adequately predict the pharmacokinetics of solifenacin in liver and renal impaired patients. Also, a better insight into the pharmacokinetic properties of solifenacin was obtained. In conclusion, the proposed semi-physiological approach is attractive for prediction of altered pharmacokinetics of compounds influenced by liver and renal disease conditions.