Dose Adjustment in Patients with Liver Cirrhosis – Comparison of Two Different Modeling Approaches

Abstract

Failure to perform adequate dose adjustment in patients with liver cirrhosis may be associated with increased toxicity. We compared the prediction of area under the curve (AUC) and clearance for the six compounds of the Basel phenotyping cocktail (caffeine, efavirenz, flurbiprofen, omeprazole, metoprolol, and midazolam) using a well‐known physiology‐based pharmacokinetic approach (physiologically‐based pharmacokinetic [PBPK] approach, Simcyp) and a novel top‐down method based on the systemic clearance in healthy volunteers adjusted for markers of liver and renal dysfunction (“top‐down approach”). With few exceptions, plasma concentration‐time curves were accurately predicted by the PBPK approach. In comparison to the measured AUC and clearance of these drugs in patients with liver cirrhosis and healthy controls, except for efavirenz, the estimates of both approaches were within two standard deviations of the mean for total and free drug concentrations. For both approaches, a correction factor for dose adjustment in patients with liver cirrhosis could be calculated for the drugs administered. AUCs calculated using the adjusted doses were comparable to the AUCs measured in control subjects, with slightly more accurate predictions generated by the PBPK approach. For drugs with a free fraction < 50%, predictions using free drug concentrations were more accurate than with total drug concentrations. In conclusion, both methods provided good qualitative predictions of the changes by liver cirrhosis in the pharmacokinetics of the six compounds investigated. The top‐down approach is easier to implement but the PBPK approach predicted changes in drug exposure more accurately than the top‐down approach and provided reliable estimates for plasma concentrations.

Effect of changes in metabolic enzymes and transporters on drug metabolism in the context of liver disease: Impact on pharmacokinetics and drug–drug interactions

“…Recently, the PBPK approach and a top‐down method, based upon adjustment of clearance in healthy volunteers and patients with liver cirrhosis, evaluated the prediction of area under the curve (AUC) for the Basel phenotyping cocktail. Both methods predicted the effect upon AUC reasonably well, but the PBPK approach predicted changes in drug exposure more accurately 137 …”