title: Utilizing drug-drug interaction prediction tools during drug development: enhanced decision making based on clinical risk.
abstract: Several reports in the literature present the utility and value of in vitro drug-metabolizing enzyme inhibition data to predict in vivo drug-drug interactions in humans. A retrospective analysis has been conducted for 26 GlaxoSmithKline (GSK) drugs and drug candidates for which in vitro inhibition parameters have been determined, and clinical drug interaction information, from a total of 46 studies, is available. The dataset, for drugs with a diverse range of physiochemical properties, included both reversible and potentially irreversible cytochrome P450 inhibitors for which in vitro inhibition parameters (IC(50) or K(I)/k(inact) as appropriate) were determined using standardized methodologies. Mechanistic static models that differentiated reversible and metabolism-dependent inhibition, and also considered the contribution of intestinal metabolism for CYP3A4 substrates, were applied to estimate the magnitude of the interactions. Several pharmacokinetic parameters, including total C(max), unbound C(max), as well as estimates of hepatic inlet and liver concentration, were used as surrogates for the inhibitor concentration at the enzyme active site. The results suggest that estimated unbound liver concentration or unbound hepatic inlet concentration, with consideration of intestinal contribution, offered the most accurate predictions of drug-drug interactions (occurrence and magnitude) for the drugs in this dataset. When used with epidemiological information on comedication profiles for a given therapeutic area, these analyses offer a quantitative risk assessment strategy to inform the necessity of excluding specific comedications in early clinical studies and the ultimate requirement for clinical drug-drug interaction studies. This strategy has significantly reduced the number of clinical drug interaction studies performed at GSK.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, PTS DMPK, Park Road, Ware, Herts, United Kingdom SG12 0DP. Carole.E.Shardlow@gsk.com
authors.forename: Carole E
authors.initials: CE
authors.lastname: Shardlow
authors.forename: Grant T
authors.initials: GT
authors.lastname: Generaux
authors.forename: Christopher C
authors.initials: CC
authors.lastname: MacLauchlin
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Pons
authors.forename: Konstantine W
authors.initials: KW
authors.lastname: Skordos
authors.forename: Jackie C
authors.initials: JC
authors.lastname: Bloomer
mesh_terms: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism; D003658:Decision Making, Computer-Assisted; D055808:Drug Discovery / Q000379:methods*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005069:Evaluation Studies as Topic; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008956:Models, Chemical; D012189:Retrospective Studies; D018570:Risk Assessment
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System