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

Abstract

Background and ObjectiveChronic 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.MethodsAfter 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.ResultsThe 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.ConclusionThere 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...

Optimizing the Clinical Use of Carvedilol in Liver Cirrhosis Using a Physiologically Based Pharmacokinetic Modeling Approach

“…The PBPK model presented here is a modified and extended version of the model developed and evaluated previously in healthy adults [9]; however, after modifications with regard to the assigned clearance due to glucuronidation. In the previous report [9], clearance due to glucuronidation was assigned collectively as 20 % of the total drug clearance that was calculated using the retrograde model of enzyme kinetics within Simcyp Ò .…”

“…In the previous report [9], clearance due to glucuronidation was assigned collectively as 20 % of the total drug clearance that was calculated using the retrograde model of enzyme kinetics within Simcyp Ò . There are, however, reports stating the involvement of UGT1A1, UGT2B4, and UGT2B7 enzymes in the glucuronidation of carvedilol [30,31], along with their relative contributions [31].…”

“…In fact, reports about the use of PBPK models to predict drug absorption, distribution, metabolism, and elimination (ADME) and drug dosing in healthy and diseased populations (liver cirrhosis, renal failure, and chronic heart failure, etc.) have been previously published [5][6][7][8][9]. Among these are two PBPK-cirrhosis models that were modified with relevant pathophysiological changes with respect to the severity of liver cirrhosis (classified with a Child-Pugh [CP] score A-C) to predict the PK profiles of various drugs [6,7].…”

Predicting Stereoselective Disposition of Carvedilol in Adult and Pediatric Chronic Heart Failure Patients by Incorporating Pathophysiological Changes in Organ Blood Flows-A Physiologically Based Pharmacokinetic Approach

“…A physiologically based PK (PBPK) model incorporating reduced hepatic and renal blood flows has been used previously to predict PK of racemic carvedilol in adult and pediatric CHF patients (Rasool et al, 2015). However, the reductions in blood flow to limbs, adipose, skin, and muscle tissues, which can additionally affect the drug distribution and hence the plasma concentration of the drug, were not yet incorporated in the previously reported carvedilol-CHF model (Rasool et al, 2015).…”

“…However, the reductions in blood flow to limbs, adipose, skin, and muscle tissues, which can additionally affect the drug distribution and hence the plasma concentration of the drug, were not yet incorporated in the previously reported carvedilol-CHF model (Rasool et al, 2015). Keeping in mind that carvedilol is administered as a racemic mixture of R and S enantiomers, which have ;twofold difference in their F, the organ blood flow reductions occurring in CHF can affect the disposition of both in a stereoselective fashion.…”