Comment on: “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”

Excerpt

Heart failure is associated with impaired cardiac output and tissue perfusion, thereby resulting in altered drug disposition and exposure [1‐4]. In a recent issue of Clinical Pharmacokinetics, Rasool et al. [5] reported the worthwhile attempt to develop physiologically-based pharmacokinetic (PBPK) models for carvedilol in adult patients with chronic heart failure by incorporating pathophysiological alterations in hepatic and renal blood flows, and subsequently used the PBPK models to predict oral pharmacokinetics of carvedilol in pediatric patients by accounting for age-related physiological differences. The authors found that the incorporation of decreased hepatic and renal blood flows into their PBPK models resulted in a marked improvement in the predictive accuracy of the carvedilol PBPK models in adult patients with chronic heart failure. On the other hand, the authors noticed that incorporating known changes in hepatic and renal blood flows did not lead to any improvement in the predictive accuracy of the PBPK models for carvedilol in infants (aged 0.1–1 years) with chronic heart failure, and emphasized the knowledge gaps related to gastrointestinal physiology (namely ‘gastric and intestinal pH, bile secretion, transporters and gut fluid dynamics’) in infant populations which may influence the predictive performance of their PBPK models for infant patients. Ultimately, the authors concluded that their PBPK models “could be extended to other high-extraction drugs in heart failure patients”. …