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• W1993437269 endingPage "828" @default.
• W1993437269 startingPage "803" @default.
• W1993437269 abstract "Abstract Methods for prediction of hepatic clearance (CLH) in man have been evaluated. A physiologically-based in-vitro to in-vivo (PB-IVIV) method with human unbound fraction in blood (fu,bl) and hepatocyte intrinsic clearance (CLint)-data has a good rationale and appears to give the best predictions (maximum ∼2-fold errors; &lt; 25% errors for half of CL-predictions; appropriate ranking). Inclusion of an empirical scaling factor is, however, needed, and reasons include the use of cryopreserved hepatocytes with low activity, and inappropriate CLint- and fu,bl-estimation methods. Thus, an improvement of this methodology is possible and required. Neglect of fu,bl or incorporation of incubation binding does not seem appropriate. When microsome CLint-data are used with this approach, the CLH is underpredicted by 5- to 9-fold on average, and a 106-fold underprediction (attrition potential) has been observed. The poor performance could probably be related to permeation, binding and low metabolic activity. Inclusion of scaling factors and neglect of fu,bl for basic and neutral compounds improve microsome predictions. The performance is, however, still not satisfactory. Allometry incorrectly assumes that the determinants for CLH relate to body weight and overpredicts human liver blood flow rate. Consequently, allometric methods have poor predictability. Simple allometry has an average overprediction potential, &gt; 2-fold errors for ∼1/3 of predictions, and 140-fold underprediction to 5800-fold overprediction (potential safety risk) range. In-silico methodologies are available, but these need further development. Acceptable prediction errors for compounds with low and high CLH should be ∼50 and ∼10%, respectively. In conclusion, it is recommended that PB-IVIV with human hepatocyte CLint and fu,bl is applied and improved, limits for acceptable errors are decreased, and that animal CLH-studies and allometry are avoided." @default.
• W1993437269 created "2016-06-24" @default.
• W1993437269 creator A5047119000 @default.
• W1993437269 date "2007-06-01" @default.
• W1993437269 modified "2023-10-16" @default.
• W1993437269 title "Prediction of human pharmacokinetics—evaluation of methods for prediction of hepatic metabolic clearance" @default.
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