title: Evaluation of drug-drug interactions for oncology therapies: in vitro-in vivo extrapolation model-based risk assessment.
abstract: OBJECTIVE
  Understanding drug-drug interactions (DDI) is a critical part of the drug development process as polypharmacy has become commonplace in many therapeutic areas including the cancer patient population. The objectives of this study were to investigate cytochrome P450 (CYP)-mediated DDI profiles available for therapies used in the oncology setting and evaluate how models based on in vitro-in vivo extrapolation performed in predicting CYP-mediated DDI risk.
  
  
  METHODS
  A dataset of 125 oncology therapies was collated using drug label and approval history information, incorporating in vitro and clinical PK data. The predictive accuracy of the basic and net effect mechanistic static models was assessed using this oncology drug dataset, for both victim and perpetrator potential of CYP3A-mediated DDI.
  
  
  RESULTS
  The incidence of CYP3A-mediated interaction potential was 47%, 22% and 11% for substrates, inhibitors and inducers, respectively. The basic models for precipitants gave conservative predictions with no false negatives, whilst the mechanistic static models provided reasonable quantitative predictions (2.3-3-fold error). Further analysis revealed that incorporating DDI at the level of the intestine was in most cases over-predicting interaction magnitude due to overestimates of the rate and extent of oral absorption of the precipitant. Quantifying victim DDI potential was also demonstrated using fmCYP3A estimates from ketoconazole clinical DDI studies to predict the magnitude of interaction on co-administration with the CYP3A inducer, rifampicin (1.6-3.3 fold error).
  
  
  CONCLUSIONS
  This work illustrates the utility and limitations of current DDI risk assessment approaches applied to a range of contemporary anti-cancer agents, and discusses the implications for therapeutic combination strategies.
authors.affiliation: Epizyme, Inc., 400 Technology Square, Cambridge, MA, USA.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Waters
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065701:Cytochrome P-450 CYP3A Inducers / Q000009:adverse effects; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000009:adverse effects; D062313:Databases, Pharmaceutical; D017277:Drug Approval; D004347:Drug Interactions; D004348:Drug Labeling; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008495:Medical Oncology; D008954:Models, Biological; D019338:Polypharmacy; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D000970:Antineoplastic Agents; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A
keywords: CYP induction; CYP inhibition; CYP3A; anti-cancer therapy; drug interactions; pharmacokinetics