A Population PK Analysis of Nebivolol and Valsartan in Combination Therapy
E. Niclas Jonsson (1), Mats O. Magnusson (1), Chun Lin Chen (2), Timothy Carrothers (2), Parviz Ghahramani (2)
(1) Pharmetheus, Uppsala, Sweden, (2) Forest Research Institute, Jersey City, NJ, USA
Objectives: To characterize the population PK of nebivolol (d-nebivolol, l-nebivolol, nebivolol glucuronide) and valsartan as single drugs and as a fixed-dose combination (FDC), to characterize covariate relations and to generate predictions for PKPD modeling of sitting cuff-measured and 24-hour ambulatory blood pressure.
Methods: Population PK models were developed in NONMEM V7.2.0  based on data from six Phase 1 studies and one Phase 3 study. A total of 893 individuals and 21066 observations were included in the analysis. The valsartan, d-nebivolol and l-nebivolol PK data were described by two-compartment models with first order absorption and lag-time. The nebivolol glucuronide model was driven by the observed total nebivolol and the predicted d-nebivolol and l-nebivolol concentrations, and was a two-compartment model with serial zero-first order absorption. The basic models were used as the basis for covariate model development. The impact of the statistically significant covariates on the area under the curve (AUC) and maximum concentration (Cmax) were evaluated using univariate predictions. The ratios of AUC and Cmax were computed for the 10th and 90th percentiles, or extreme categories for categorical covariates, of the observed covariate distribution.
Results: The final models provided adequate descriptions of the data as judged by graphical diagnostics and visual predictive checks. The covariates that were associated with the largest AUC and Cmax ratios were study phase (1 versus 3) for valsartan and isoenzyme of CYP2D6 for d-nebivolol, l-nebivolol and nebivolol glucuronide. The CL/F for a typical extensive CYP2D6 metaboliser with mono-therapy were 14.2, L/h, 2098 L/h, 1179 L/h and 40.7 L/h for valsartan, d-nebivolol, l-nebivolol and nebivolol glucuronide, respectively. The corresponding values for poor metabolisers were 14.2 L/h, 97.7 L/h, 26.0 L/h and 3.8 L/h. There was no impact of co-administration on CL/F for d- and l-nebivolol while there was a ~20% increase for valsartan and nebivolol glucuronide.
Conclusion: The population PK of nebivolol and valsartan as single drugs or as FDC was successfully described by two-compartment models. A number of covariates were found statistically significant but only a subset had any substantial impact on AUC and Cmax. For d- and l-nebivolol the impact of co-administration was minimal and for valsartan and nebivolol glucuronide it was moderate.
 Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.