Abstract
1. Focusing on the genetic similarity of CYP3A subfamily enzymes (CYP3A4 and CYP3A5) between monkeys and humans, we have attempted to provide a single-species approach to predicting human hepatic clearance (CLh) of CYP3A4 substrates using pharmacokinetic parameters in cynomolgus monkeys following intravenous administrations.
2. Hepatic intrinsic clearance (CLint,h) of six CYP3A4 substrates (alprazolam, clonazepam, diltiazem, midazolam, nifedipine, and quinidine), covering a wide range of clearance, in monkeys correlated well with that cited in literature for humans (R = 0.90) with a simple equation of Y = 0.165X (Y: human CLint,h, X: monkey CLint,h, represented in mL/min/kg).
3. To verify the predictability of human CLint,h, monkey CLint,h of a test set of CYP3A4 substrates cited in literature (dexamethasone, nifedipine, midazolam, quinidine, tacrolimus, and verapamil) was applied to the equation and human CLint,h was calculated. The human CLint,h of all the substrates was predicted within 3-fold error (fold error: 0.35–2.77).
4. The predictability of human CLh by our method was superior to common in vivo prediction methods (allometry and liver blood flow method). These results suggest that human hepatic clearance of CYP3A4 substrates can be predicted by applying cynomolgus monkey CLint,h obtained following intravenous administrations in each laboratory to the simple equation.
Acknowledgements
We thank Naomi Tomita and Hiroko Igarashi in Chugai Pharmaceutical Co., Ltd., for technical support in preparing in vivo PK samples. We acknowledge the useful advice of Chugai Editing Services in the preparation of this article.
Declaration of interest
The authors report no declaration of interest.