Background: During drug development, it is an important safety factor to identify the potential of new molecular entities to become a victim of drug-drug interactions (DDIs). In preclinical development, however, anticipation of clinical DDIs remains challenging due to the lack of in vivo human pharmacokinetic data.
Methods: We applied a recently developed in vitro-in vivo extrapolation method, including hepatic metabolism and transport processes, herein referred to as the Extended Clearance Concept Classification System (ECCCS). The human hepatic clearances and the victim DDI potentials were predicted for atorvastatin, cerivastatin, fluvastatin, lovastatin acid, pitavastatin, pravastatin, rosuvastatin, and simvastatin acid.
Results: Hepatic statin clearances were well-predicted by the ECCCS with six out of eight clearances projected within a two-fold deviation to reported values. In addition, worst-case DDI predictions were projected for each statin. Based on the ECCCS class assignment (4 classes), the mechanistic interplay of metabolic and transport processes, resulting in different DDI risks, was well-reflected by our model. Furthermore, predictions of clinically observed statins DDIs in combination with relevant perpetrator drugs showed good quantitative correlations with clinical observations.
Conclusions: The ECCCS represents a powerful tool to anticipate the DDI potential of victim drugs based on in vitro drug metabolism and transport data.
The authors wish to acknowledge the many Novartis Drug Metabolism and Pharmacokinetic scientists of Basel, Switzerland, who have supported this work. Special thanks go to Francis Heitz for technical assistance.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
1. 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.Search in Google Scholar
2. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med 2002;346:539–40.Search in Google Scholar
3. Li J, Volpe DA, Wang Y, Zhang W, Bode C, Owen A, et al. Use of transporter knockdown Caco-2 cells to investigate the in vitro efflux of statin drugs. Drug Metab Dispos 2011;39:1196–202.Search in Google Scholar
4. 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.Search in Google Scholar
5. Umehara K, Camenisch G. Novel in vitro-in vivo extrapolation (IVIVE) method to predict hepatic organ clearance in rat. Pharm Res 2012;29:603–17.Search in Google Scholar
6. Camenisch G, Umehara K. Predicting human hepatic clearance from in vitro drug metabolism and transport data: a scientific and pharmaceutical perspective for assessing drug-drug interactions. Biopharm Drug Dispos 2012;33:179–94.Search in Google Scholar
7. Benet LZ, Amidon GL, Barends DM, Lennernas H, Polli JE, Shah VP, et al. The use of BDDCS in classifying the permeability of marketed drugs. Pharm Res 2008;25:483–8.Search in Google Scholar
8. Sharma P, Butters CJ, Smith V, Elsby R, Surry D. Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins. Eur J Pharm Sci 2012;47:244–55.Search in Google Scholar
9. 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.Search in Google Scholar
10. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 2006;80:565–81.Search in Google Scholar
11. Fujino H, Saito T, Tsunenari Y, Kojima J, Sakaeda T. Metabolic properties of the acid and lactone forms of HMG-CoA reductase inhibitors. Xenobiotica 2004;34:961–71.Search in Google Scholar
12. Kunze A, Huwyler J, Camenisch G, Poller B. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos 2014;42:1514–21.Search in Google Scholar
13. Boulenc X, Barberan O. Metabolic-based drug-drug interactions prediction, recent approaches for risk assessment along drug development. Drug Metabol Drug Interact 2011;26:147–68.Search in Google Scholar
14. Einolf HJ. Comparison of different approaches to predict metabolic drug-drug interactions. Xenobiotica 2007;37:1257–94.Search in Google Scholar
15. Elsby R, Hilgendorf C, Fenner K. Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it’s not just about OATP1B1. Clin Pharmacol Ther 2012;92:584–98.Search in Google Scholar
16. Carlile DJ, Zomorodi K, Houston JB. Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver: studies with induced livers involving diazepam. Drug Metab Dispos 1997;25:903–11.Search in Google Scholar
17. Swift B, Pfeifer ND, Brouwer KL. Sandwich-cultured hepatocytes: an in vitro model to evaluate hepatobiliary transporter-based drug interactions and hepatotoxicity. Drug Metab Rev 2010;42:446–71.Search in Google Scholar
18. Backman JT, Kyrklund C, Kivisto KT, Wang JS, Neuvonen PJ. Plasma concentrations of active simvastatin acid are increased by gemfibrozil. Clin Pharmacol Ther 2000;68:122–9.Search in Google Scholar
19. Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate. Clin Pharmacol Ther 2001;69:340–5.Search in Google Scholar
20. Prueksaritanont T, Tang C, Qiu Y, Mu L, Subramanian R, Lin JH. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002;30:1280–7.Search in Google Scholar
21. Shitara Y, Hirano M, Sato H, Sugiyama Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil. J Pharmacol Exp Ther 2004;311:228–36.Search in Google Scholar
22. US FDA Drug Label. Available at: . 2014.Search in Google Scholar
23. Prueksaritanont T, Zhao JJ, Ma B, Roadcap BA, Tang C, Qiu Y, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002;301:1042–51.Search in Google Scholar
24. Matsushima S, Maeda K, Kondo C, Hirano M, Sasaki M, Suzuki H, et al. Identification of the hepatic efflux transporters of organic anions using double-transfected Madin-Darby canine kidney II cells expressing human organic anion-transporting polypeptide 1B1 (OATP1B1)/multidrug resistance-associated protein 2, OATP1B1/multidrug resistance 1, and OATP1B1/breast cancer resistance protein. J Pharmacol Exp Ther 2005;314:1059–67.Search in Google Scholar
25. Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet 2001;40:263–81.Search in Google Scholar
26. Bi YA, Qiu X, Rotter CJ, Kimoto E, Piotrowski M, Varma MV, et al. Quantitative assessment of the contribution of sodium-dependent taurocholate co-transporting polypeptide (NTCP) to the hepatic uptake of rosuvastatin, pitavastatin and fluvastatin. Biopharm Drug Dispos 2013;34:452–61.Search in Google Scholar
27. 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.Search in Google Scholar
28. Fujino H, Yamada I, Shimada S, Yoneda M, Kojima J. Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: human UDP-glucuronosyltransferase enzymes involved in lactonization. Xenobiotica 2003;33:27–41.Search in Google Scholar
29. Hirano M, Maeda K, Matsushima S, Nozaki Y, Kusuhara H, Sugiyama Y. Involvement of BCRP (ABCG2) in the biliary excretion of pitavastatin. Mol Pharmacol 2005;68:800–7.Search in Google Scholar
30. Corsini A, Ceska R. Drug-drug interactions with statins: will pitavastatin overcome the statins’ Achilles’ heel? Curr Med Res Opin 2011;27:1551–62.Search in Google Scholar
31. Liu Y, She M, Wu Z, Dai R. The inhibition study of human UDP-glucuronosyltransferases with cytochrome P450 selective substrates and inhibitors. J Enzyme Inhib Med Chem 2011;26:386–93.Search in Google Scholar
32. Lau YY, Okochi H, Huang Y, Benet LZ. Multiple transporters affect the disposition of atorvastatin and its two active hydroxy metabolites: application of in vitro and ex situ systems. J Pharmacol Exp Ther 2006;316:762–71.Search in Google Scholar
33. Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002;300:1036–45.Search in Google Scholar
34. El-Sheikh AA, Greupink R, Wortelboer HM, van den Heuvel JJ, Schreurs M, Koenderink JB, et al. Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4. Transl Res 2013;162:398–409.Search in Google Scholar
35. Ho RH, Tirona RG, Leake BF, Glaeser H, Lee W, Lemke CJ, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology 2006;130:1793–806.Search in Google Scholar
36. Xia CQ, Liu N, Miwa GT, Gan LS. Interactions of cyclosporin a with breast cancer resistance protein. Drug Metab Dispos 2007;35:576–82.Search in Google Scholar
37. Annaert P, Ye ZW, Stieger B, Augustijns P. Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1. Xenobiotica 2010;40:163–76.Search in Google Scholar
38. Eagling VA, Back DJ, Barry MG. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997;44:190–4.Search in Google Scholar
39. Everett DW, Chando TJ, Didonato GC, Singhvi SM, Pan HY, Weinstein SH. Biotransformation of pravastatin sodium in humans. Drug Metab Dispos 1991;19:740–8.Search in Google Scholar
40. Sasaki M, Suzuki H, Ito K, Abe T, Sugiyama Y. Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and multidrug resistance-associated protein 2 (MRP2/ABCC2). J Biol Chem 2002;277:6497–503.Search in Google Scholar
41. Nakagomi-Hagihara R, Nakai D, Tokui T. Inhibition of human organic anion transporter 3 mediated pravastatin transport by gemfibrozil and the metabolites in humans. Xenobiotica 2007;37:416–26.Search in Google Scholar
42. Kyrklund C, Backman JT, Neuvonen M, Neuvonen PJ. Gemfibrozil increases plasma pravastatin concentrations and reduces pravastatin renal clearance. Clin Pharmacol Ther 2003;73: 538–44.Search in Google Scholar
43. Kunze A, Huwyler J, Poller B, Gutmann H, Camenisch G. In vitro-in vivo extrapolation method to predict human renal clearance of drugs. J Pharm Sci 2014;103:994–1001.Search in Google Scholar
44. Niemi M, Arnold KA, Backman JT, Pasanen MK, Godtel-Armbrust U, Wojnowski L, et al. Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet Genomics 2006;16:801–8.Search in Google Scholar
45. Martin PD, Warwick MJ, Dane AL, Hill SJ, Giles PB, Phillips PJ, et al. Metabolism, excretion, and pharmacokinetics of rosuvastatin in healthy adult male volunteers. Clin Ther 2003;25:2822–35.Search in Google Scholar
46. 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.Search in Google Scholar
47. Verhulst A, Sayer R, De Broe ME, D’Haese PC, Brown CD. Human proximal tubular epithelium actively secretes but does not retain rosuvastatin. Mol Pharmacol 2008;74:1084–91.Search in Google Scholar
48. Windass AS, Lowes S, Wang Y, Brown CD. The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther 2007;322:1221–7.Search in Google Scholar
49. Pfeifer ND, Bridges AS, Ferslew BC, Hardwick RN, Brouwer KL. Hepatic basolateral efflux contributes significantly to rosuvastatin disposition II: characterization of hepatic elimination by basolateral, biliary, and metabolic clearance pathways in rat isolated perfused liver. J Pharmacol Exp Ther 2013;347:737–45.Search in Google Scholar
50. Pfeifer ND, Yang K, Brouwer KL. Hepatic basolateral efflux contributes significantly to rosuvastatin disposition I: characterization of basolateral versus biliary clearance using a novel protocol in sandwich-cultured hepatocytes. J Pharmacol Exp Ther 2013;347:727–36.Search in Google Scholar
51. Martin PD, Warwick MJ, Dane AL, Brindley C, Short T. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther 2003;25:2553–63.Search in Google Scholar
52. Jamei M, Bajot F, Neuhoff S, Barter Z, Yang J, Rostami-Hodjegan A, et al. A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine. Clin Pharmacokinet 2014;53:73–87.Search in Google Scholar
53. 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.Search in Google Scholar
54. Kirchheiner J, Kudlicz D, Meisel C, Bauer S, Meineke I, Roots I, et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 2003;74:186–94.Search in Google Scholar
The online version of this article (DOI: 10.1515/dmdi-2015-0003) offers supplementary material, available to authorized users.
©2015 by De Gruyter