A mechanism-based integrated pharmacokinetic enzyme model describing the time course and magnitude of @entity109 -mediated enzyme induction in the XXXX .

@entity69062 @entity11042 @entity36158 @entity109 @entity35 @entity7771 @entity2671
PURPOSE: To characterize the magnitude, time course, and specificity of @entity109 (PB)-mediated enzyme induction, and further, to develop an integrated pharmacokinetic (PK)-enzyme model describing the changes in the activities of CYP enzymes as well as in the PK of PB. METHODS: PB plasma concentrations and in vitro activities of several CYP enzymes were measured in @entity35 treated with PB between 0 and 14 days. A PB PK-enzyme induction model was developed using the program NONMEM: . RESULTS: PB treatment both induces and reduces the activity of CYP enzymes by stimulating the enzymes' formation or elimination rates. Certain CYP enzymes affected the PB PK through autoinduction. The half-life of the induction process was estimated to be 2 days for @entity7771 , @entity69062 , and @entity36158 , and 3 days for @entity2671 producing enzymes. The @entity11042 activity was rapidly reduced by PB treatment. A lag time for the PB autoinduction was observed. This lag time is explained by the rate difference between induction and reduction in CYP activities. CONCLUSION: To our knowledge, this is the first example of an induction model that simultaneously describes plasma PK and in vitro data. It does so by integrating the bidirectional interaction between drug and enzymes in a mechanistic manner.
