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.

Abstract

Chronic heart failure (CHF) is a systemic low perfusion syndrome resulting from impairment in the pumping function of the heart. The decrease in blood supply to body organs can potentially affect the pharmacokinetics (PK) of the drugs being administered. Carvedilol is administered as a racemic mixture and undergoes extensive stereoselective first pass metabolism. For such a drug, the pathophysiological changes occurring in CHF can have a profound impact on PK, and thus the resulting pharmacodynamic response, of both enantiomers. The aim of the current work was to predict stereoselective disposition of carvedilol after incorporating the pathophysiological changes in CHF into a whole-body physiologically based PK model using Simcyp, and to scale that model to pediatric CHF patients on a physiologic basis to investigate whether the same changes in the adult model can also be adopted for children. The developed model has successfully described PK of carvedilol enantiomers in healthy adults and in patients after the incorporation of reduced organ blood flows, as seen by the visual predictive checks and the calculated observed/predicted ratios for all PK parameters of interest. In contrast to adults, pediatric patients up to 12 years of age were better described without the reductions in organ blood flow, whereas older pediatric patients were better described after incorporating organ blood flow reductions. These findings indicate that the incorporated blood flow reductions in the adult model cannot be directly adopted in pediatrics, at least for the young ones; however, to draw definite conclusions, more data are still needed.