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A new approach to predicting human hepatic clearance of CYP3A4 substrates using monkey pharmacokinetic data.

Xenobiotica. 2012 Nov 15;

Authors: Ogawa K, Kato M, Houjo T, Ishigai M


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 (CL(h)) of CYP3A4 substrates using pharmacokinetic parameters in cynomolgus monkeys following intravenous administrations. 2. Hepatic intrinsic clearance (CL(int,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 CL(int,h), X: monkey CL(int,h), represented in mL/min/kg). 3. To verify the predictability of human CL(int,h), monkey CL(int,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 CL(int,h) was calculated. The human CL(int,h) of all the substrates was predicted within 3-fold error (fold error: 0.35-2.77). 4. The predictability of human CL(h) 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 CL(int,h) obtained following intravenous administrations in each laboratory to the simple equation.

PMID: 23153054 [PubMed - as supplied by publisher]