title: Quantitative prediction and clinical observation of a CYP3A inhibitor-based drug-drug interactions with MLN3897, a potent C-C chemokine receptor-1 antagonist.
abstract: A novel in vitro model was recently developed in our laboratories for the prediction of magnitude of clinical pharmacokinetic drug-drug interactions (DDIs), based on reversible hepatic cytochrome P450 (P450) inhibition. This approach, using inhibition data from human hepatocytes incubated in human plasma, and quantitative P450 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. In addition, 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 crossover design, with ketoconazole (200 mg b.i.d.) or fluconazole (400 mg once a day), while receiving MLN3897. Administration of MLN3897 and ketoconazole led to an average 8.28-fold increase in area under the curve of plasma concentration-time plot (AUC) of MLN3897 at steady state, compared with the 8.33-fold increase predicted from the in vitro data. Similarly for fluconazole, an average increase of 3.93-fold in AUC was observed for MLN3897 in comparison with 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA. chuang.lu@mpi.com
authors.forename: Chuang
authors.initials: C
authors.lastname: Lu
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balani
authors.forename: Mark G
authors.initials: MG
authors.lastname: Qian
authors.forename: Shimoga R
authors.initials: SR
authors.lastname: Prakash
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Ducray
authors.forename: Lisa L
authors.initials: LL
authors.lastname: von Moltke
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008954:Models, Biological; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*
chemical_list: C515300:CCR1 protein, human; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D054389:Receptors, CCR1; D015725:Fluconazole; D007654:Ketoconazole