Die Pharmazie · 2026
A Simple Quantitative Method for the Prediction of Exposure of Drugs in Subjects With Varying Degrees of Hepatic Impairment.
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Mahmood Iftekhar
Аннотация
BACKGROUND: Hepatic impairment can alter the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs due to the liver's reduced ability to metabolize drugs. The objective of this study was to develop a simple quantitative method using the Child-Pugh classification scoring system to predict the area under the curve (AUC) of drugs in subjects with mild, moderate, and severe hepatic impairment.
METHODS: In this study, from healthy subjects, the AUC of 64, 76, and 51 drugs in subjects with mild, moderate, and severe hepatic impairment, respectively, were predicted. The drugs used in this analysis are those that are extensively metabolized in the liver by the cytochrome P-450 system (phase I metabolism). Child-Pugh scores were used to classify varying degrees of hepatic impairment. The scores <5 (no hepatic impairment), and 5, 7, and 10 are the scores from where the Child-Pugh score begins for mild, moderate, and severe hepatic impairment, respectively. In this analysis, a Child-Pugh score of 4 was assigned to healthy subjects. The AUC of a drug in subjects with mild hepatic impairment was predicted as follows: AUC in healthy subjects × (5/4)^0.75, where 5 is the Child-Pugh score in subjects with mild hepatic impairment, and the exponent 0.75 is the exponent of basal metabolic rate or clearance. A similar approach for the prediction of the AUC of drugs was taken in subjects with moderate and severe hepatic impairment. The predicted AUC values in subjects with mild, moderate, and severe hepatic impairment were compared with the observed values obtained from dedicated clinical trials.
RESULTS: In subjects with mild, moderate, and severe hepatic impairment 96.9%, 97.4%, and 82.4% drugs were within 0.5-2-fold prediction error, respectively. No drug was predicted with >2-fold prediction error.
CONCLUSIONS: Overall, the results of the study indicated that the proposed method, in its predictive performance, was fairly accurate for the prediction of the AUC of a drug in subjects with varying degrees of hepatic impairment. The proposed method will be helpful in the selection of appropriate dose(s) of drugs in subjects with varying degrees of hepatic impairment for clinical trials or, in some cases, in clinical settings (especially, in mild or moderate hepatic impairment).
METHODS: In this study, from healthy subjects, the AUC of 64, 76, and 51 drugs in subjects with mild, moderate, and severe hepatic impairment, respectively, were predicted. The drugs used in this analysis are those that are extensively metabolized in the liver by the cytochrome P-450 system (phase I metabolism). Child-Pugh scores were used to classify varying degrees of hepatic impairment. The scores <5 (no hepatic impairment), and 5, 7, and 10 are the scores from where the Child-Pugh score begins for mild, moderate, and severe hepatic impairment, respectively. In this analysis, a Child-Pugh score of 4 was assigned to healthy subjects. The AUC of a drug in subjects with mild hepatic impairment was predicted as follows: AUC in healthy subjects × (5/4)^0.75, where 5 is the Child-Pugh score in subjects with mild hepatic impairment, and the exponent 0.75 is the exponent of basal metabolic rate or clearance. A similar approach for the prediction of the AUC of drugs was taken in subjects with moderate and severe hepatic impairment. The predicted AUC values in subjects with mild, moderate, and severe hepatic impairment were compared with the observed values obtained from dedicated clinical trials.
RESULTS: In subjects with mild, moderate, and severe hepatic impairment 96.9%, 97.4%, and 82.4% drugs were within 0.5-2-fold prediction error, respectively. No drug was predicted with >2-fold prediction error.
CONCLUSIONS: Overall, the results of the study indicated that the proposed method, in its predictive performance, was fairly accurate for the prediction of the AUC of a drug in subjects with varying degrees of hepatic impairment. The proposed method will be helpful in the selection of appropriate dose(s) of drugs in subjects with varying degrees of hepatic impairment for clinical trials or, in some cases, in clinical settings (especially, in mild or moderate hepatic impairment).