A Prediction Model of Drug Exposure in Cirrhotic Patients According to Child-Pugh Classification

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Abstract

Background and Objective

Prediction of drug clearance in liver cirrhosis patients is currently based on in vitroin vivo extrapolation and physiologically-based pharmacokinetic models. No static model for this purpose has been described. The objectives of this study were to (1) derive a static model for predicting drug exposure in cirrhotic patients, and (2) to evaluate the model on a large set of published data.

Methods

The impact of cirrhosis was characterized by the ratio of the total and unbound drug area under the concentration-time curve (AUC) in cirrhotic patients to the AUC measured in healthy subjects These ratios were predicted for Child-Pugh classes A, B, and C. The AUC ratios observed in published data were compared with AUC ratios predicted by the model.

Results

Among 171 drugs examined, 83 published AUC ratios for 45 drugs in cirrhotic patients were available for analysis. The mean ± standard deviation relative prediction error for the total and unbound AUC ratios was 0.22 ± 0.58 and 0.24 ± 0.56, respectively. There were four outliers among the 83 predicted values. Simulations showed that the prediction error was negligible provided that the hepatic extraction coefficient was less than 0.8.

Conclusions

For mild and moderate cirrhosis (classes A and B), the predicted unbound AUC ratio is typically approximately 2 and 3.5, respectively, for most drugs. In the absence of data in cirrhotic patients, the drug dose might be empirically reduced by these factors. In severe cirrhosis (class C), our model may help clinicians to adjust their prescriptions.

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