Abstract
Time-dependent inactivation (TDI) of human cytochromes P450 3A4 (CYP3A4) is a major cause of clinical drug drug interactions (DDIs). Human liver microsomes (HLM) are commonly used as an enzyme source for evaluating the inhibition of CYP3A4 by new chemical entities (NCEs). The inhibition data can be then extrapolated to assess the risk of human DDIs. Using this approach, under- and over-predictions of in vivo DDIs have been observed. In the present study, human hepatocytes were used as an alternative to HLM. Hepatocytes incorporate the effects of other mechanisms of drug metabolism and disposition (i.e. phase II enzymes and transporters) that may modulate the effects of TDI on clinical DDIs. The in vitro potency (KI and kinact) of five known CYP3A4 TDI drugs (clarithromycin, diltiazem, erythromycin, verapamil and troleandomycin) was determined in HLM (pooled, n=20) and hepatocytes from two donors (D1 and D2) and the results were extrapolated to predict in vivo DDIs using a SimCYP population trial-based simulator. In comparison to observed DDIs, the predictions derived from HLM appeared to be over-estimated. The predictions based on TDI measured in hepatocytes were better correlated with the DDIs (n = 37) observed in vivo (R2 = 0.601, D1 and 0.740, D2) than those from HLM (R2 = 0.451). In addition, using hepatocytes a greater proportion of the predictions were within a 2-fold range of the clinical DDIs compared to using HLM. These results suggest that DDI predictions from CYP3A4 TDI kinetics in hepatocytes could provide an alternative approach to balance HLM-based predictions that can sometimes substantially over-estimate DDIs and possibly lead to erroneous conclusions about clinical risks.
- clinical pharmacokinetics
- CYP inhibition
- CYP3A
- drug-drug interactions
- enzyme kinetics
- in vitro-in vivo prediction
- in vitro-in vivo scaling
- inactivation
- mechanism-based inhibition
Footnotes
- Received November 3, 2008.
- Accepted September 16, 2009.
- The American Society for Pharmacology and Experimental Therapeutics