QUANTITATIVE PREDICTION AND CLINICAL OBSERVATION OF A CYP3A INHIBITOR-BASED DRUG - DRUG INTERACTIONS WITH MLN3897, A POTENT CCR1 ANTAGONIST. The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] Journal article | | Title | QUANTITATIVE PREDICTION AND CLINICAL OBSERVATION OF A CYP3A INHIBITOR-BASED DRUG - DRUG INTERACTIONS WITH MLN3897, A POTENT CCR1 ANTAGONIST. | | Author(s) | Lu C, Balani SK, Qian MG, Prakash SR, Ducray PS, von Moltke LL | | Institution | Millennium Pharmaceuticals, Inc. | | Source | J Pharmacol Exp Ther 2009 Nov 4. | | Abstract | A novel in vitro model was recently developed in our labs for the prediction of magnitude of clinical pharmacokinetic drug-drug interactions (DDIs), based on reversible hepatic CYP inhibition. This approach, using inhibition data from human hepatocytes incubated in human plasma, and quantitative CYP phenotyping data from hepatic microsomal incubations, successfully predicted DDIs for 15 marketed drugs with ketoconazole, a strong competitive inhibitor of CYP3A4/5 generally used to demonstrate a "worst case scenario" for CYP3A inhibition. Additionally, this approach was successfully extended to DDI predictions with the moderate competitive CYP3A inhibitor fluconazole for nine marketed drugs. In the current report, the general applicability of the model has been demonstrated by prospectively predicting the degree of inhibition, and then conducting DDI studies in the clinic for an investigational CCR1 antagonist, MLN3897 which is cleared predominantly by CYP3A. The clinical studies involved treatment of healthy volunteers (n= 17-20), in a cross-over design, with ketoconazole (200 mg BID) or fluconazole (400 mg QD) while receiving MLN3897. Administration of MLN3897 and ketoconazole led to an average 8.28-fold increase in AUC of MLN3897 at steady-state, compared to the 8.33-fold increase predicted from the in vitro data. Similarly for fluconazole, an average increase of 3.90-fold in AUC was observed for MLN3897 in comparison to a predicted value of 3.26-fold. Thus, our model reliably predicted the exposure changes for MLN3897 in interaction studies with competitive CYP3A inhibitors in humans, further strengthening the utility of our in vitro model. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19889796 |
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