Pharmacokinetics in the Fontan circulation: a multi-organ puzzle

Patients with Fontan circulation represent a pharmacologically distinct population in whom the haemodynamic consequences of single-ventricle physiology alter every phase of drug disposition in ways that current prescribing practice systematically fails to account for. Fontan-associated liver disease suppresses hepatic CYP enzyme activity and reduces first-pass metabolism, increasing bioavailability and systemic exposure of drugs. Hypoalbuminaemia from protein-losing enteropathy elevates the free fraction of highly protein-bound agents, rendering standard total drug concentration targets unreliable. Reduced cardiac output contracts the volume of distribution of hydrophilic drugs and diminishes renal perfusion, while creatinine-based glomerular filtration rate equations systematically overestimate true renal function due to reduced skeletal muscle mass, leading to inadequate dose reduction for renally cleared agents. These disturbances are predicted to affect the pharmacokinetics of every major cardiovascular drug class prescribed in this population, including anticoagulants, antiarrhythmics, neurohormonal antagonists, and pulmonary vasodilators, although direct Fontan-specific pharmacokinetic data remain scarce and confirm these effects for only a minority of agents, with dosing largely extrapolated from non-congenital populations. This review examines the mechanistic basis of pharmacokinetic alterations across drug disposition, evaluate available drug-class evidence, and outlines a research agenda including physiologically based pharmacokinetic modelling, registry-embedded studies, and dedicated inclusion of Fontan patients in future trials.