Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidance from Regulatory Agencies: Focus on Downregulation, CYP2C Induction, and CYP2B6 Positive Control

Abstract

The European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (PMDA), and the Food and Drug Administration (FDA) have issued guidelines for the conduct of drug-drug interaction studies. To examine the applicability of these regulatory recommendations specifically for induction, a group of scientists, under the auspices of the Drug Metabolism Leadership Group of the Innovation and Quality (IQ) Consortium, formed the Induction Working Group (IWG). A team of 19 scientists, from 16 of the 39 pharmaceutical companies that are members of the IQ Consortium and two Contract Research Organizations reviewed the recommendations, focusing initially on the current EMA guidelines. Questions were collated from IQ member companies as to which aspects of the guidelines require further evaluation. The EMA was then approached to provide insights into their recommendations on the following: 1) evaluation of downregulation, 2) in vitro assessment of CYP2C induction, 3) the use of CITCO as the positive control for CYP2B6 induction by CAR, 4) data interpretation (a 2-fold increase in mRNA as evidence of induction), and 5) the duration of incubation of hepatocytes with test article. The IWG conducted an anonymous survey among IQ member companies to query current practices, focusing specifically on the aforementioned key points. Responses were received from 19 companies. All data and information were blinded before being shared with the IWG. The results of the survey are presented, together with consensus recommendations on downregulation, CYP2C induction, and CYP2B6 positive control. Results and recommendations related to data interpretation and induction time course will be reported in subsequent articles.

Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

“…34,35 The study of downregulation of drug-metabolizing enzymes presents a few challenges, some of which include (1) variability in drug response in human hepatocyte experiments partly due to differences in culture conditions; (2) loss of enzymatic activity in hepatocyte cultures over time; (3) lack of positive controls for downregulation; and (4) the facts that observed changes in mRNA may be due to cytotoxicity, and in vitro findings do not always translate into clinical effects. 39 The prolonged change in pharmacokinetics observed in our study is similar to those previously reported in DDIs with warfarin 8,10 and other CYP2C9 substrates, 27,28 and transcriptional changes can take time to disappear. We were unable to find a suitable nonclinical model to study an event that takes this long to manifest.…”

Does In Vitro Cytochrome P450 Downregulation Translate to In Vivo Drug‐Drug Interactions? Preclinical and Clinical Studies With 13‐cis‐Retinoic Acid

“…After treatment of patients with rheumatoid arthritis with anti-IL-6 antibodies, the exposure of CYP2C9, CYP2C19, and CYP3A4 substrates decreased. 27,28 However, existing information 5,23 coupled with the data collected in this study, suggests that unlike cytokine-mediated CYP downregulation, small molecule-mediated CYP downregulation in vitro does not necessarily translate to in vivo decreases in enzyme activity. It is likely that the lack of translation of in vitro downregulation to in vivo DDI is dependent on the mechanism of regulation of enzyme expression, and more studies are needed to identify mechanisms of CYP downregulation.…”

“…On study day 2, subjects were given 13cisRA to be taken as 40 mg b.i.d. with food for 13 days (study days [2][3][4][5][6][7][8][9][10][11][12][13][14]. The 13cisRA capsules were purchased (as Isotretinoin) by the University of Washington Investigational Pharmacy, which dispensed all study medications.…”

“…4 The Induction Working Group of the IQ Consortium recently reported that mRNA downregulation is relatively frequently observed in hepatocyte studies, (16 of 17 companies surveyed had observed downregulation in routine induction studies), and in cases when downregulation was observed, the maximal decrease was commonly > 50%. 5 However, the clinical translation of these findings is not known.…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…A screening method for CYP induction often uses 96‐well plated HHEP (e.g., 70,000 cells at seeding), includes 2‐day treatment with test compound at three concentrations (e.g., 1, 10, and 100 μM, if solubility allows), and measures mRNA and activity changes of the enzymes (Table , Figure ) (Fahmi, Kish, Boldt, & Obach, ; Hariparsad et al, ; Kenny et al, ; Sane et al, ). Positive controls of 20 μM of omeprazole for CYP1A2, 1 mM phenobarbital for CYP2B6, and 10 μM rifampin for CYP3A4 are typically used in induction screening experiments.…”