A Physiologically Based Pharmacokinetic Drug–Disease Model to Predict Carvedilol Exposure in Adult and Paediatric Heart Failure Patients by Incorporating Pathophysiological Changes in Hepatic and Renal Blood Flows

BACKGROUND AND OBJECTIVE: Chronic diseases are associated with pathophysiological changes that could have profound impacts on drug pharmacokinetic behaviour, with a potential need to modify the administered drug therapy. It is important to acknowledge that most patients with chronic illnesses do not have a single, predominant condition but suffer from multiple comorbidities. The rapid advancement in physiologically based pharmacokinetic (PBPK) modelling, as well as the increasing quantitative knowledge of disease-related pathophysiological changes, facilitate building of drug–disease models. However, there are only a few published examples of PBPK models incorporating the pathophysiological changes that occur with chronic diseases. The objective of this study was to develop PBPK models that incorporate the haemodynamic changes in hepatic and renal blood flows occurring in chronic heart failure (CHF) and to evaluate these changes in adults and children, using carvedilol as a model drug. METHODS: After a comprehensive literature search to select the model input parameters, two PBPK models were developed. Model 1 was based on human liver and intestinal microsome clearances, and model 2 was based on clearance by specific cytochrome P450 enzymes. After evaluation of both models in healthy adults, the reduced hepatic and renal blood flows were incorporated into the developed models to predict carvedilol exposure in the adult CHF population. The adult carvedilol models were scaled down to children by using Simcyp(®) (Simcyp Ltd, Sheffield, UK). In order to show the impact of reduced organ blood flows on carvedilol disposition, the predictions in the CHF population were made with and without reductions in organ blood flows. RESULTS: The predictions made by both models in healthy adults were comparable and within the 2-fold error range. In adults with CHF, the mean observed/predicted ratio [ratio((Obs/Pred))] for oral clearance (CL/F) without reductions in organ blood flows was outside the 2-fold error range, i.e. 0.34 (95 % confidence interval [CI] 0.31–0.37), with use of both models. The mean CL/F ratio((Obs/Pred)) values after incorporation of reduced organ blood flows were 1.0 (95 % CI 0.92–1.08) and 0.95 (95 % CI 0.88–1.03) with use of models 1 and 2, respectively. The mean ratio((Obs/Pred)) values for the pharmacokinetic parameters were not improved after incorporation of reduced blood flows in paediatric patients, except in those above 17 years of age, who were categorized according to the New York Heart Association classification of CHF, where the CL/F ratio((Obs/Pred)) values in two patients were closer to unity. CONCLUSION: There was a strong connection between a decrease in hepatic clearance of carvedilol and an increase in the severity of CHF, especially in adults and in paediatric patients above 17 years of age. The incorporated reductions in hepatic and renal blood flows occurring in moderate and severe CHF patients resulted in improved predictions of carvedilol exposure. The developed models can be extended to predict exposures of drugs with high hepatic extraction in the CHF population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40262-015-0253-7) contains supplementary material, which is available to authorized users.