Abstract
Recently, the US Food and Drug Administration and European Medicines Agency have issued new guidance for industry on drug interaction studies, which outline comprehensive recommendations on a broad range of in vitro and in vivo studies to evaluate drug–drug interaction (DDI) potential. This paper aims to provide an overview of these new recommendations and an in-depth scientifically based perspective on issues surrounding some of the recommended approaches in emerging areas, particularly, transporters and complex DDIs. We present a number of theoretical considerations and several case examples to demonstrate complexities in applying (1) the proposed transporter decision trees and associated criteria for studying a broad spectrum of transporters to derive actionable information and (2) the recommended model-based approaches at an early stage of drug development to prospectively predict DDIs involving time-dependent inhibition and mixed inhibition/induction of drug metabolizing enzymes. We hope to convey the need for conducting DDI studies on a case-by-case basis using a holistic scientifically based interrogative approach and to communicate the need for additional research to fill in knowledge gaps in these areas where the science is rapidly evolving to better ensure the safety and efficacy of new therapeutic agents.
Similar content being viewed by others
References
Huang SM, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol. 2008;48:662–70.
European Medicines Agency (EMA), Committee for Human Medicinal Products for Human use (CHMP). Concept paper/recommendation on the need for revision of (CHMP) Note for guidance on the investigation of drug interactions. July 2008.
The European Agency for the Evaluation of Medicinal Products (EMEA), Committee for Proprietary Medicinal Products (CPMP). Note for guidance on the investigation on drug interactions. December 1997.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry, drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. February 2012.
European Medicine Agency (EMA), Committee for Human Medicinal Products (CHMP). Guideline on the investigation of drug interactions. 21 June 2012.
Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, et al. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9:215–36.
European Medicines Agency (EMA), Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical investigation of the pharmacokinetics of therapeutic proteins. January 2007.
Hulskotte EGJ, Xuan F, van Zutven MGJA, O’Mara E, Galitz L. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin. 16th Annual Meeting of HEP DART; December 4–8, 2011; Koloa, Hawaii.
Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors: drug–drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112:71–105.
He YJ, Zhang W, Chen Y, Guo D, Tu JH, Xu LY, et al. Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism. Clin Chim Acta. 2009;405:49–52.
Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 2008;47:570–8.
Lee JE, van Heeswijk R, Alves K, Smith F, Garg V. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother. 2011;55:4569–74.
Huang L, Be X, Tchaparian EH, Colletti AE, Roberts J, Langley M, et al. Deletion of Abcg2 has differential effects on excretion and pharmacokinetics of probe substrates in rats. J Pharmacol Exp Ther. 2012;343:316–24.
Backman JT, Luurila H, Neuvonen M, Neuvonen PJ. Rifampin markedly decreases and gemfibrozil increases the plasma concentrations of atorvastatin and its metabolites. Clin Pharmacol Ther. 2005;78:154–67.
Jonker JW, Wagenaar E, Mol CA, Buitelaar M, Koepsell H, Smit JW, et al. Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (Oct1 [Slc22a1]) gene. Mol Cell Biol. 2001;21:5471–7.
Iusuf D, Sparidans RW, van Esch A, Hobbs M, Kenworthy KE, van de Steeg E, et al. Organic anion-transporting polypeptides 1a/1b control the hepatic uptake of pravastatin in mice. Mol Pharm. 2012;9:2497–504.
Vlaming ML, Pala Z, van Esch A, Wagenaar E, de Waart DR, van de Wetering K, et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin Cancer Res. 2009;15:3084–93.
Tsuda M, Terada T, Ueba M, Sato T, Masuda S, Katsura T, et al. Involvement of human multidrug and toxin extrusion 1 in the drug interaction between cimetidine and metformin in renal epithelial cells. J Pharmacol Exp Ther. 2009;329:185–91.
Ito S, Kusuhara H, Yokochi M, Toyoshima J, Inoue K, Yuasa H, et al. Competitive inhibition of the luminal efflux by multidrug and toxin extrusions, but not basolateral uptake by organic cation transporter 2, is the likely mechanism underlying the pharmacokinetic drug–drug interactions caused by cimetidine in the kidney. J Pharmacol Exp Ther. 2012;340:393–403.
de Vries NA, Zhao J, Kroon E, Buckle T, Beijnen JH, van Tellingen O. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clin Cancer Res. 2007;13:6440–9.
Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM. Inhibition of P-glycoprotein-mediated drug transport: a unifying mechanism to explain the interaction between digoxin and quinidine. Circulation. 1999;99:552–7.
Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9:203–14.
Agarwal S, Mittapalli RK, Zellmer DM, Gallardo JL, Donelson R, Seiler C, et al. Active efflux of dasatinib from the brain limits efficacy against murine glioblastoma: broad implications for the clinical use of molecularly targeted agents. Mol Cancer Ther. 2012;11:2183–92.
Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, et al. Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008;7:2280–7.
Zaher H, Meyer zu Schwabedissen HE, Tirona RG, Cox ML, Obert LA, Agrawal N, et al. Targeted disruption of murine organic anion-transporting polypeptide 1b2 (Oatp1b2/Slco1b2) significantly alters disposition of prototypical drug substrates pravastatin and rifampin. Mol Pharmacol. 2008;74:320–9.
Chen C, Stock JL, Liu X, Shi J, Van Deusen JW, DiMattia DA, et al. Utility of a novel Oatp1b2 knockout mouse model for evaluating the role of Oatp1b2 in the hepatic uptake of model compounds. Drug Metab Dispos. 2008;36:1840–5.
Jonker JW, Wagenaar E, Van Eijl S, Schinkel AH. Deficiency in the organic cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in mice abolishes renal secretion of organic cations. Mol Cell Biol. 2003;23:7902–8.
Lau YY, Huang Y, Frassetto L, Benet LZ. Effect of OATP1B transporter inhibition on the pharmacokinetics of atorvastatin in healthy volunteers. Clin Pharmacol Ther. 2007;81:194–204.
Zheng HX, Huang Y, Frassetto LA, Benet LZ. Elucidating rifampin’s inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite. Clin Pharmacol Ther. 2009;85:78–85.
Frymoyer A, Shugarts S, Browne M, Wu AHB, Frassetto L, Benet LZ. Effect of single-dose rifampin on the pharmacokinetics of warfarin in healthy volunteers. Clin Pharmacol Ther. 2010;88:540–7.
Bihorel S, Camenisch G, Lemaire M, Scherrmann JM. Modulation of the brain distribution of imatinib and its metabolites in mice by valspodar, zosuquidar and elacridar. Pharm Res. 2007;24:1720–8.
Oostendorp RL, Buckle T, Beijnen JH, van Tellingen O, Schellens JHM. The effect of Pgp (Mdr1a/1b), BCRP (Bcrp1) and Pgp/BCRP inhibitors on the in vivo absorption, distribution, metabolism and excretion of imatinib. Investig New Drugs. 2009;27:31–40.
van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35:692–706.
Lemahieu WP, Hermann M, Asberg A, Verbeke K, Holdaas H, Vanrenterghem Y, et al. Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus. Am J Transplant. 2005;5:2236–43.
Binet I, Wallnofer A, Weber C, Jones R, Thiel G. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int. 2000;57:224–31.
Kajosaari LI, Niemi M, Neuvonen M, Laitila J, Neuvonen PJ, Backman JT. Cyclosporine markedly raises the plasma concentrations of repaglinide. Clin Pharmacol Ther. 2005;78:388–99.
Menochet K, Kenworthy KE, Houston JB, Galetin A. Simultaneous assessment of uptake and metabolism in rat hepatocytes: a comprehensive mechanistic model. J Pharmacol Exp Ther. 2012;341:2–15.
Menochet K, Kenworthy KE, Houston JB, Galetin. Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes. Drug Metab Dispos. 2012;40:1744–56.
Yoshida K, Maeda K, Sugiyama Y. Transporter-mediated drug–drug interactions involving OATP substrates: predictions based on in vitro inhibition studies. Clin Pharmacol Ther. 2012;91:1053–64.
Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4:481–508.
Martin PD, Warwick MJ, Dane AL, Hill ST, Giles PB, Phillips PJ, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther. 2003;25:2822–35.
Kitamura S, Maeda K, Wang Y, Sugiyama Y. Involvement of multiple transporters in the hepatobiliary transport of rosuvastatin. Drug Metab Dispos. 2008;36:2014–23.
Tomlinson B, Hu M, Lee VWY, Lui SSH, Chu TTW, Poon EWM, et al. ABCG2 Polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010;87:558–62.
Schneck DW, Birmingham BK, Zalikowski JA, Mitchell PD, Wang Y, Martin PD, et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin Pharmacol Ther. 2004;75:455–63.
Allred AJ, Bowen CJ, Park JW, Peng B, Williams DD, Wire MB, et al. Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol. 2011;72:321–9.
Pham PA, la Porte CJ, Lee LS, van Heeswijk R, Sabo JP, Elgadi MM, et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother. 2009;53:4385–92.
Martin PD, Warwick MJ, Dane AL, Brindley C, Short T. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther. 2003;25:2553–653.
Busti AJ, Bain AM, Hall 2nd RG, Bedimo RG, Leff RD, Meek C, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol. 2008;51:605–10.
Prueksaritanont T, Subramanian R, Fang X, Ma B, Qiu Y, Lin JH, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30:505–12.
Prueksaritanont T, Tang C, Que Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280–7.
Chu XY, Strauss JR, Mariano MA, Li J, Newton DJ, Cai X, et al. Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). J Pharmacol Exp Ther. 2006;317:579–89.
Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev. 2011;63:157–81.
Pasanen MK, Neuvonen M, Neuvonen PJ, Niemi M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet Genomics. 2006;16:873–9.
Pasanen MK, Fredrikson H, Neuvonen PJ, Niemi M. Different effects of SLCO1B1 polymorphism on the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2007;82:726–33.
Keskitalo JE, Pasanen MK, Neuvonen PJ, Niemi M. Different effects of the ABCG2 c.421C>A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics. 2009;10:1617–24.
Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86:197–203.
Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004;25:193–200.
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41:89–295.
Wang Y-H, Trucksis M, McElwee JJ, Wong PH, Maciolek C, Thompson CD, et al. UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study. Clin Pharmacol Ther. 2012;92:96–102.
Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A. 1997;94:4028–33.
Sugimoto H, Hirabayashi H, Kimura Y, Furuta A, Amano N, Moriwaki T. Quantitative investigation of the impact of P-glycoprotein inhibition on drug transport across blood–brain barrier in rats. Drug Metab Dispos. 2011;39:8–14.
Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM. Highlights from the International Transporter Consortium second workshop. Clin Pharmacol Ther. 2012;92:553–6.
Chu X, Cai X, Cui D, Tang C, Ghosal A, Chan G, et al. In vitro assessment of drug–drug interaction potential of boceprevir associated with drug metabolizing enzymes and transporters. Drug Metab Dispos. 2013. doi:10.1124/dmd.112.049668.
Noe J, Portmann R, Brun ME, Funk C. Substrate-dependent drug–drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3. Drug Metab Dispos. 2007;35:1308–14.
Kindla J, Muller F, Mieth M, Fromm MF, Konig J. Influence of non-steroidal anti-inflammatory drugs on organic anion transporting polypeptide (OATP) 1B1-and OATP1B3-mediated drug transport. Drug Metab Dispos. 2011;39:1047–53.
Gui C, Obaidat A, Chaguturu R, Hagenbuch B. Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr Chem Genomics. 2010;4:1–8.
Shitara Y, Nagamatsu Y, Wada S, Sugiyama Y, Horie T. Long-lasting inhibition of the transporter-mediated hepatic uptake of sulfobromophthalein by cyclosporin a in rats. Drug Metab Dispos. 2009;37:1172–8.
Amundsen R, Christensen H, Zabihyan B, Asberg A. Cyclosporine A, but not tacrolimus, shows relevant inhibition of organic anion-transporting protein 1B1-mediated transport of atorvastatin. Drug Metab Dispos. 2010;38:1499–504.
Shitara Y, Takeuchi K, Nagamatsu Y, Wada S, Sugiyama Y, Horie T. Long-lasting inhibitory effects of cyclosporin A, but not tacrolimus, on OATP1B1- and OATP1B3-mediated uptake. Drug Metab Pharmacokinet. 2012;27:368–78.
Vaidyanathan J, Arya V, Agarwal S, de LT VM, Zhao P, Huang S-M, et al. What criteria may be appropriate in determining the need for in vivo evaluation of a new molecular entity’s (NME’S) potential to inhibit OATP1B (organic anion transporting polypeptide 1B1). Clin Pharmacol Ther. 2012;91(Suppl1):S53–3.
Einolf HJ. Comparison of different approaches to predict metabolic drug–drug interactions. Xenobiotica. 2007;37:1257–94.
Kato M, Shitara Y, Sato H, Yoshisue K, Hirano M, Ikeda T, et al. The quantitative prediction of CYP-mediated drug interaction by physiologically based pharmacokinetic modeling. Pharm Res. 2008;25:1891–901.
Almond LM, Yang J, Jamei M, Tucker GT, Rostami-Hodjegan A. Towards a quantitative framework for the prediction of DDIs arising from cytochrome P450 induction. Curr Drug Metab. 2009;10:420–32.
Wang Y-H. Confidence assessment of the Simcyp time-based approach and a static mathematical model in predicting clinical drug–drug interactions for mechanism-based CYP3A inhibitors. Drug Metab Dispos. 2010;38:1094–104.
Shardlow CE, Generaux GT, MacLauchlin CC, Pons N, Skordos KW, Bloomer JC. Utilizing drug–drug interaction prediction tools during drug development: enhanced decision making based on clinical risk. Drug Metab Dispos. 2011;39:2076–84.
Fenneteau F, Poulin P, Nekka F. Physiologically based predictions of the impact of inhibition of intestinal and hepatic metabolism on human pharmacokinetics of CYP3A substrates. J Pharm Sci. 2010;99:486–514.
Fahmi OA, Hurst S, Plowchalk D, Cook J, Guo F, Youdim K, et al. Comparison of different algorithms for predicting clinical drug–drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction. Drug Metab Dispos. 2009;37:1658–66.
Vieira MLT, Kirby B, Ragueneau-Majlessi I, Galetin A, Grime K, Obach RS, et al. Evaluation of FDA and EMA models’ cut-off values for predicting CYP3A inhibition: a collaborative effort between academic, regulatory, and IQC pharmaceutical scientists. Clin Pharmacol Ther. 2012;91(Suppl1):S48–8.
Friedman EJ, Fraser IP, Wang YH, Bergman AJ, Li CC, Larson PJ, et al. Effect of different durations and formulations of diltiazem on the single-dose pharmacokinetics of midazolam: how long do we go? J Clin Pharmacol. 2011;51:1561–70.
Ito K, Iwatsubo T, Kanamitsu S, Ueda K, Suzuki H, Sugiyama Y. Prediction of pharmacokinetic alterations caused by drug–drug interactions: metabolic interaction in the liver. Pharmacol Rev. 1998;50:387–412.
Kiser JJ, Burton JR, Anderson PL, Everson GT. Review and management of drug interactions with boceprevir and telaprevir. Hepatology. 2012;55:1620–8.
Garg V, Chandorkar G, Farmer HF, Smith F, Alves K, van Heeswijk RP. Effect of telaprevir on the pharmacokinetics of midazolam and digoxin. J Clin Pharmacol. 2012;52:1566–73.
Loi CM, Young M, Randinitis E, Vassos A, Koup JR. Clinical pharmacokinetics of troglitazone. Clin Pharmacokinet. 1999;37:90–104.
Yeo KR, Walsky RL, Jamei M, Rostami-Hodjegan A, Tucker GT. Prediction of time-dependent CYP3A4 drug–drug interactions by physiologically based pharmacokinetic modelling: impact of inactivation parameters and enzyme turnover. Eur J Pharm Sci. 2011;43:160–73.
Reitman ML, Chu X, Cai X, Yabut J, Venkatasubramanian R, Zajic S, et al. Rifampin’s acute inhibitory and chronic inductive drug interactions: experimental and model-based approaches to drug–drug interaction trial design. Clin Pharmacol Ther. 2011;89:234–42.
Sanchez RI, Wang R, Newton DJ, Bakhtiar R, Lu P, et al. Cytochrome P450 3A4 is the major enzyme involved in the metabolism of substance P receptor antogonist aprepitant. Drug Metab Dispos. 2004;32:1287–92.
Pascussi JM, Gerbal-Chaloin S, Drocourt L, Maurel P, Vilarem MJ. The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of nuclear and steroid receptors. Biochim Biophys Acta. 2003;1619:243–53.
Chen Y, Kissling G, Negishi M, Goldstein JA. The nuclear receptors constitutive androstane receptor and pregnane X receptor cross-talk with hepatic nuclear factor 4alpha to synergistically activate the human CYP2C9 promoter. J Pharmacol Exp Ther. 2005;314:1125–33.
Xu L, Chen Y, Pan Y, Skiles GL, Shou M. Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. Drug Metab Dispos. 2009;37:2330–9.
Parkinson A, Kazmi F, Buckley DB, Yerino P, Ogilvie BW, Paris BL. System-dependent outcomes during the evaluation of drug candidates as inhibitors of cytochrome P450 (CYP) and uridine diphosphate glucuronosyltransferase (UGT) enzymes: human hepatocytes versus liver microsomes versus recombinant enzymes. Drug Metab Dispos. 2010;25:16–27.
Chen Y, Liu L, Monshouwer M, Fretland AJ. Determination of time-dependent inactivation of CYP3A4 in cryopreserved human hepatocytes and assessment of human drug–drug interactions. Drug Metab Dispos. 2011;39:2085–92.
Yan Z, Caldwell GW. The current status of time dependent CYP inhibition assay and in silico drug–drug interaction predictions. Curr Top Med Chem. 2012;12:1291–7.
DiMasi JA, Feldman L, Seckler A, Wilson A. Trends in risks associated with new drug development: success rates for investigational drugs. Clin Pharmacol Ther. 2010;87:272–7.
ACKNOWLEDGMENTS
We would like to thank Drs. Ying-Hong Wang, Jairam Palamanda, Prajakti Kothare, Raymond Evers, and David Cutler for their help and valuable inputs, and Drs. Jane Croft Harrelson, Nancy Agrawal, Richard Morrison, and James Yergey for their critical review of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
ESM 1
DOC 187 kb
Rights and permissions
About this article
Cite this article
Prueksaritanont, T., Chu, X., Gibson, C. et al. Drug–Drug Interaction Studies: Regulatory Guidance and An Industry Perspective. AAPS J 15, 629–645 (2013). https://doi.org/10.1208/s12248-013-9470-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-013-9470-x