title: Application of Static Models to Predict Midazolam Clinical Interactions in the Presence of Single or Multiple Hepatitis C Virus Drugs.
abstract: Asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are three drugs developed for the treatment of chronic hepatitis C virus infection. Here, we evaluated the CYP3A4 induction potential of each drug, as well as BCV-M1 (the major metabolite of BCV), in human hepatocytes by measuring CYP3A4 mRNA alteration. The induction responses were quantified as induction fold (mRNA fold change) and induction increase (mRNA fold increase), and then fitted with four nonlinear regression algorithms. Reversible inhibition and time-dependent inhibition (TDI) on CYP3A4 activity were determined to predict net drug-drug interactions (DDIs). All four compounds were CYP3A4 inducers and inhibitors, with ASV demonstrating TDI. The curve-fitting results demonstrated that fold increase is a better assessment to determine kinetic parameters for compounds inducing weak responses. By summing the contribution of each inducer, the basic static model was able to correctly predict the potential for a clinically meaningful induction signal for single or multiple perpetrators, but with over prediction of the magnitude. With the same approach, the mechanistic static model improved the prediction accuracy of DCV and BCV when including both induction and inhibition effects, but incorrectly predicted the net DDI effects for ASV alone or triple combinations. The predictions of ASV or the triple combination could be improved by only including the induction and reversible inhibition but not the ASV CYP3A4 TDI component. Those results demonstrated that static models can be applied as a tool to help project the DDI risk of multiple perpetrators using in vitro data.
authors.affiliation: Pharmaceutical Candidate Optimization, Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Yaofeng
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Pharmaceutical Candidate Optimization, Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Pharmaceutical Candidate Optimization, Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Chang
authors.affiliation: Pharmaceutical Candidate Optimization, Research and Development, Bristol-Myers Squibb, Princeton, New Jersey.
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.affiliation: Pharmaceutical Candidate Optimization, Research and Development, Bristol-Myers Squibb, Princeton, New Jersey Wenying.Li@BMS.com.
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
mesh_terms: D000465:Algorithms; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D001711:Biotransformation; D002219:Carbamates; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000009:adverse effects / Q000627:therapeutic use*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D007546:Isoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008874:Midazolam / Q000009:adverse effects / Q000627:therapeutic use*; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011759:Pyrrolidines; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives
chemical_list: C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D002219:Carbamates; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D007093:Imidazoles; D007211:Indoles; D007546:Isoquinolines; D011759:Pyrrolidines; D012333:RNA, Messenger; D013449:Sulfonamides; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014633:Valine; C549273:daclatasvir; D008874:Midazolam; C571889:asunaprevir