PMID- 31439574 OWN - NLM STAT- MEDLINE DCOM- 20200601 LR - 20200601 IS - 1521-009X (Electronic) IS - 0090-9556 (Linking) VI - 47 IP - 10 DP - 2019 Oct TI - Perspectives from the Innovation and Quality Consortium Induction Working Group on Factors Impacting Clinical Drug-Drug Interactions Resulting from Induction: Focus on Cytochrome 3A Substrates. PG - 1206-1221 LID - 10.1124/dmd.119.087270 [doi] AB - A recent publication from the Innovation and Quality Consortium Induction Working Group collated a large clinical data set with the goal of evaluating the accuracy of drug-drug interaction (DDI) prediction from in vitro data. Somewhat surprisingly, comparison across studies of the mean- or median-reported area under the curve ratio showed appreciable variability in the magnitude of outcome. This commentary explores the possible drivers of this range of outcomes observed in clinical induction studies. While recommendations on clinical study design are not being proposed, some key observations were informative during the aggregate analysis of clinical data. Although DDI data are often presented using median data, individual data would enable evaluation of how differences in study design, baseline expression, and the number of subjects contribute. Since variability in perpetrator pharmacokinetics (PK) could impact the overall DDI interpretation, should this be routinely captured? Maximal induction was typically observed after 5-7 days of dosing. Thus, when the half-life of the inducer is less than 30 hours, are there benefits to a more standardized study design? A large proportion of CYP3A4 inducers were also CYP3A4 inhibitors and/or inactivators based on in vitro data. In these cases, using CYP3A selective substrates has limitations. More intensive monitoring of changes in area under the curve over time is warranted. With selective CYP3A substrates, the net effect was often inhibition, whereas less selective substrates could discern induction through mechanisms not susceptible to inhibition. The latter included oral contraceptives, which raise concerns of reduced efficacy following induction. Alternative approaches for modeling induction, such as applying biomarkers and physiologically based pharmacokinetic modeling (PBPK), are also considered. SIGNIFICANCE STATEMENT: The goal of this commentary is to stimulate discussion on whether there are opportunities to optimize clinical drug-drug interaction study design. The overall aim is to reduce, understand and contextualize the variability observed in the magnitude of induction across reported clinical studies. A large clinical CYP3A induction dataset was collected and further analyzed to identify trends and gaps. Reporting individual victim PK data, characterizing perpetrator PK and including additional PK assessments for mixed-mechanism perpetrators may provide insights into how these factors impact differences observed in clinical outcomes. The potential utility of biomarkers and PBPK modeling are discussed in considering future directions. CI - Copyright (c) 2019 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Ramsden, Diane AU - Ramsden D AUID- ORCID: 0000-0003-2994-0728 AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.) dramsden@alnylam.com. FAU - Fung, Conrad AU - Fung C AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). FAU - Hariparsad, Niresh AU - Hariparsad N AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). FAU - Kenny, Jane R AU - Kenny JR AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). FAU - Mohutsky, Michael AU - Mohutsky M AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). FAU - Parrott, Neil J AU - Parrott NJ AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). FAU - Robertson, Sarah AU - Robertson S AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). FAU - Tweedie, Donald J AU - Tweedie DJ AD - Alnylam Pharmaceuticals, Cambridge, Massachusetts (D.R.); Vertex Pharmaceuticals, Boston, Massachusetts (C.F., N.H., S.R.); Genentech, South San Francisco, California (J.R.K.); Eli Lilly and Company, Indianapolis, Indiana (M.M.); Roche Innovation Center, Basel, Switzerland (N.J.P.); and Merck & Co., Inc., Kenilworth, New Jersey (D.T.). LA - eng PT - Journal Article DEP - 20190822 PL - United States TA - Drug Metab Dispos JT - Drug metabolism and disposition: the biological fate of chemicals JID - 9421550 RN - 0 (Cytochrome P-450 CYP3A Inducers) RN - 0 (Cytochrome P-450 CYP3A Inhibitors) RN - EC 1.14.14.1 (Cytochrome P-450 CYP3A) RN - EC 1.14.14.55 (CYP3A4 protein, human) SB - IM MH - Biological Variation, Population MH - *Clinical Trials as Topic MH - Cytochrome P-450 CYP3A/*metabolism MH - Cytochrome P-450 CYP3A Inducers/administration & dosage/*pharmacokinetics MH - Cytochrome P-450 CYP3A Inhibitors/administration & dosage/*pharmacokinetics MH - Dose-Response Relationship, Drug MH - Drug Interactions MH - Female MH - Half-Life MH - Humans MH - Male MH - Research Design EDAT- 2019/08/24 06:00 MHDA- 2020/06/02 06:00 CRDT- 2019/08/24 06:00 PHST- 2019/03/22 00:00 [received] PHST- 2019/08/06 00:00 [accepted] PHST- 2019/08/24 06:00 [pubmed] PHST- 2020/06/02 06:00 [medline] PHST- 2019/08/24 06:00 [entrez] AID - dmd.119.087270 [pii] AID - 10.1124/dmd.119.087270 [doi] PST - ppublish SO - Drug Metab Dispos. 2019 Oct;47(10):1206-1221. doi: 10.1124/dmd.119.087270. Epub 2019 Aug 22.