Skip to main content
SpringerLink
Log in

Drug–Drug Interactions Between HMG-CoA Reductase Inhibitors (Statins) and Antiviral Protease Inhibitors

  • Review Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

The HMG-CoA reductase inhibitors are a class of drugs also known as statins. These drugs are effective and widely prescribed for the treatment of hypercholesterolemia and prevention of cardiovascular morbidity and mortality. Seven statins are currently available: atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin. Although these drugs are generally well tolerated, skeletal muscle abnormalities from myalgia to severe lethal rhabdomyolysis can occur. Factors that increase statin concentrations such as drug–drug interactions can increase the risk of these adverse events. Drug–drug interactions are dependent on statins’ pharmacokinetic profile: simvastatin, lovastatin and atorvastatin are metabolized through cytochrome P450 (CYP) 3A, while the metabolism of the other statins is independent of this CYP. All statins are substrate of organic anion transporter polypeptide 1B1, an uptake transporter expressed in hepatocyte membrane that may also explain some drug–drug interactions. Many HIV-infected patients have dyslipidemia and comorbidities that may require statin treatment. HIV-protease inhibitors (HIV PIs) are part of recommended antiretroviral treatment in combination with two reverse transcriptase inhibitors. All HIV PIs except nelfinavir are coadministered with a low dose of ritonavir, a potent CYP3A inhibitor to improve their pharmacokinetic properties. Cobicistat is a new potent CYP3A inhibitor that is combined with elvitegravir and will be combined with HIV-PIs in the future. The HCV-PIs boceprevir and telaprevir are both, to different extents, inhibitors of CYP3A. This review summarizes the pharmacokinetic properties of statins and PIs with emphasis on their metabolic pathways explaining clinically important drug–drug interactions. Simvastatin and lovastatin metabolized through CYP3A have the highest potency for drug–drug interaction with potent CYP3A inhibitors such as ritonavir- or cobicistat-boosted HIV-PI or the hepatitis C virus (HCV) PI, telaprevir or boceprevir, and therefore their coadministration is contraindicated. Atorvastatin is also a CYP3A substrate, but less potent drug–drug interactions have been reported with CYP3A inhibitors. Non-CYP3A-dependent statin concentrations are also affected although to a lesser extent when coadministered with HIV or HCV PIs, mainly through interaction with OATP1B1, and treatment should start with the lowest available statin dose. Effectiveness and occurrence of adverse effects should be monitored at regular time intervals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. FDA Drug safety communication: interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012. Available from http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Accessed 18 Apr 2013.

  2. Ucar M, Mjorndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Saf. 2000;22(6):441–57.

    PubMed  CAS  Google Scholar 

  3. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41(5):343–70.

    PubMed  CAS  Google Scholar 

  4. Egger SS, Ratz Bravo AE, Hess L, et al. Age-related differences in the prevalence of potential drug–drug interactions in ambulatory dyslipidaemic patients treated with statins. Drugs Aging. 2007;24(5):429–40.

    PubMed  CAS  Google Scholar 

  5. Fulton MM, Allen ER. Polypharmacy in the elderly: a literature review. J Am Acad Nurse Pract. 2005;17(4):123–32.

    PubMed  Google Scholar 

  6. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346(7):539–40.

    PubMed  Google Scholar 

  7. EMEA. Annexe II: Scientific conclusions and grounds for withdrawal of the marketing authorisations presented by the EMEA. 2002.

  8. Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase inhibitors for treatment of hyperlipidemia in patients with HIV infection. Pharmacotherapy. 2000;20(9):1066–71.

    PubMed  CAS  Google Scholar 

  9. Lewis JS II, Terriff CM, Coulston DR, et al. Protease inhibitors: a therapeutic breakthrough for the treatment of patients with human immunodeficiency virus. Clin Ther. 1997;19(2):187–214.

    PubMed  CAS  Google Scholar 

  10. Bruno R, Sacchi P, Maiocchi L, et al. Hepatotoxicity and antiretroviral therapy with protease inhibitors: a review. Dig Liver Dis. 2006;38:363–73.

    PubMed  CAS  Google Scholar 

  11. The EuroSIDA Study Group. Changing patterns of morbidity and mortality across Europe in patients infected with HIV-1. Lancet. 1998;352:1725–30.

    Google Scholar 

  12. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853–60.

    PubMed  Google Scholar 

  13. Samaras K. Metabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infection. J Antimicrob Chemother. 2008;61(2):238–45.

    PubMed  CAS  Google Scholar 

  14. Grunfeld C, Pang M, Doerrler W, et al. Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab. 1992;74(5):1045–52.

    PubMed  CAS  Google Scholar 

  15. Carr A, Samaras K, Chisholm DJ, et al. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998;351(9119):1881–3.

    PubMed  CAS  Google Scholar 

  16. Carr A, Samaras K, Thorisdottir A, et al. Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999;353(9170):2093–9.

    PubMed  CAS  Google Scholar 

  17. Danner SA, Carr A, Leonard JM, et al. A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. N Engl J Med. 1995;333(23):1528–33.

    PubMed  CAS  Google Scholar 

  18. Calza L, Manfredi R, Farneti B, et al. Incidence of hyperlipidaemia in a cohort of 212 HIV-infected patients receiving a protease inhibitor-based antiretroviral therapy. Int J Antimicrob Agents. 2003;22:54–9.

    PubMed  CAS  Google Scholar 

  19. Calza L, Manfredi R, Chiodo F. Dyslipidaemia associated with antiretroviral therapy in HIV-infected patients. J Antimicrob Chemother. 2004;53(1):10–4.

    PubMed  CAS  Google Scholar 

  20. Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks. AIDS Res Hum Retroviruses. 2012;28(10):1184–95.

    PubMed  CAS  Google Scholar 

  21. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17):1723–35.

    PubMed  Google Scholar 

  22. Mary-Krause M, Cotte L, Simon A, et al. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS. 2003;17(17):2479–86.

    PubMed  Google Scholar 

  23. Stein JH, Klein MA, Bellehumeur JL, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001;104(3):257–62.

    PubMed  CAS  Google Scholar 

  24. Dube MP, Stein JH, Aberg JA, et al. Guidelines for the evaluation and management of dyslipidemia in human immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: recommendations of the HIV Medical Association of the Infectious Disease Society of America and the Adult AIDS Clinical Trials Group. Clin Infect Dis. 2003;37(5):613–27.

    PubMed  Google Scholar 

  25. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486–97.

    Google Scholar 

  26. Program NCE. NCEP ATP III Guidelines. 2001.

  27. Stein JH, Wu Y, Kawabata H, et al. Increased use of lipid-lowering therapy in patients receiving human immunodeficiency virus protease inhibitors. Am J Cardiol. 2003;92(3):270–4.

    PubMed  Google Scholar 

  28. EASL. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011;55(2):245–64.

    Google Scholar 

  29. Chopra A, Klein PL, Drinnan T, et al. How to optimize HCV therapy in genotype 1 patients: management of side-effects. Liver Int. 2013;33(Suppl 1):30–4.

    PubMed  CAS  Google Scholar 

  30. Wilby KJ, Greanya ED, Ford JA, et al. A review of drug interactions with boceprevir and telaprevir: implications for HIV and transplant patients. Ann Hepatol. 2012;11(2):179–85.

    PubMed  CAS  Google Scholar 

  31. Ramanathan S, Mathias AA, German P, et al. Clinical pharmacokinetic and pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet. 2011;50(4):229–44.

    PubMed  CAS  Google Scholar 

  32. PubMed Health [Internet]. Bethesda (MD): National Library of Medicine (US). http://www.ncbi.nlm.nih.gov/pubmedhealth/.

  33. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 17 April 2013.

  34. European AIDS clinical society guidelines version 6.1 November 2012. http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EacsGuidelines-v6.1-2edition.pdf. Accessed 17 April 2013.

  35. Endo A, Kuroda M, Tanzawa K. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett. 1976;72(2):323–6.

    PubMed  CAS  Google Scholar 

  36. Rodwell VW, Nordstrom JL, Mitschelen JJ. Regulation of HMG-CoA reductase. Adv Lipid Res. 1976;14:1–74.

    PubMed  CAS  Google Scholar 

  37. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425–30.

    PubMed  CAS  Google Scholar 

  38. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet. 1997;32(5):403–25.

    PubMed  CAS  Google Scholar 

  39. Laufs U, Liao JK. Isoprenoid metabolism and the pleiotropic effects of statins. Curr Atheroscler Rep. 2003;5(5):372–8.

    PubMed  Google Scholar 

  40. Corsini A, Bellosta S, Baetta R, et al. New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 1999;84(3):413–28.

    PubMed  CAS  Google Scholar 

  41. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118.

    PubMed  CAS  Google Scholar 

  42. Koh KK, Sakuma I, Quon MJ. Differential metabolic effects of distinct statins. Atherosclerosis. 2011;215(1):1–8.

    PubMed  CAS  Google Scholar 

  43. Ose L, Budinski D, Hounslow N, et al. Comparison of pitavastatin with simvastatin in primary hypercholesterolaemia or combined dyslipidaemia. Curr Med Res Opin. 2009;25(11):2755–64.

    PubMed  CAS  Google Scholar 

  44. Lee SH, Chung N, Kwan J, et al. Comparison of the efficacy and tolerability of pitavastatin and atorvastatin: an 8-week, multicenter, randomized, open-label, dose-titration study in Korean patients with hypercholesterolemia. Clin Ther. 2007;29(11):2365–73.

    PubMed  CAS  Google Scholar 

  45. Weng TC, Yang YH, Lin SJ, et al. A systematic review and meta-analysis on the therapeutic equivalence of statins. J Clin Pharm Ther. 2010;35(2):139–51.

    PubMed  CAS  Google Scholar 

  46. Smith MEB, Lee NJ, Haney E, Carson S. Drug class review: HMG-CoA reductase inhibitors (statins) and fixed dose combination products containing a statin. Final report : update 5. 2009. Available from http://www.ncbi.nlm.nih.gov/books/NBK47273/pdf/TOC.pdf.

  47. Libby P, Sukhova G, Lee RT, et al. Molecular biology of atherosclerosis. Int J Cardiol. 1997;62(Suppl 2):S23–9.

    PubMed  Google Scholar 

  48. Sytkowski PA, Kannel WB, D’Agostino RB. Changes in risk factors and the decline in mortality from cardiovascular disease. The Framingham Heart Study. N Engl J Med. 1990;322(23):1635–41.

    PubMed  CAS  Google Scholar 

  49. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–39.

    PubMed  Google Scholar 

  50. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–22.

    PubMed  CAS  Google Scholar 

  51. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–7.

    PubMed  CAS  Google Scholar 

  52. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.

    PubMed  CAS  Google Scholar 

  53. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361(9364):1149–58.

    PubMed  CAS  Google Scholar 

  54. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):7–22.

    Google Scholar 

  55. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383–9.

  56. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339(19):1349–57.

  57. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001–9.

    PubMed  CAS  Google Scholar 

  58. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–59.

    PubMed  CAS  Google Scholar 

  59. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–421.

    Google Scholar 

  60. Sathasivam S, Lecky B. Statin induced myopathy. BMJ. 2008;337:a2286.

    PubMed  Google Scholar 

  61. Kashani A, Phillips CO, Foody JM, et al. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006;114(25):2788–97.

    PubMed  CAS  Google Scholar 

  62. Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403–14.

    PubMed  CAS  Google Scholar 

  63. Nichols GA, Koro CE. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther. 2007;29(8):1761–70.

    PubMed  CAS  Google Scholar 

  64. Sathasivam S. Statin induced myotoxicity. Eur J Intern Med. 2012;23(4):317–24.

    PubMed  CAS  Google Scholar 

  65. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother. 2001;35(9):1096–107.

    PubMed  CAS  Google Scholar 

  66. Chang JT, Staffa JA, Parks M, et al. Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf. 2004;13(7):417–26.

    PubMed  CAS  Google Scholar 

  67. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565–81.

    PubMed  CAS  Google Scholar 

  68. Cohen DE, Anania FA, Chalasani N. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C–81C.

    Google Scholar 

  69. Guedes AM, Neves PL. Statins for renal patients: a fiddler on the roof? Int J Nephrol. 2012;806872:1–8.

    Google Scholar 

  70. Agarwal R. Statin induced proteinuria: renal injury or renoprotection? J Am Soc Nephrol. 2004;15(9):2502–3.

    PubMed  Google Scholar 

  71. Kalaitzidis RG, Elisaf MS. The role of statins in chronic kidney disease. Am J Nephrol. 2011;34(3):195–202.

    PubMed  CAS  Google Scholar 

  72. Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–9.

    PubMed  CAS  Google Scholar 

  73. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–42.

    PubMed  CAS  Google Scholar 

  74. Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy. 2009;29(7):800–11.

    PubMed  CAS  Google Scholar 

  75. Tuccori M, Lapi F, Testi A, et al. Statin-associated psychiatric adverse events: a case/non-case evaluation of an Italian database of spontaneous adverse drug reaction reporting. Drug Saf. 2008;31(12):1115–23.

    PubMed  Google Scholar 

  76. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci. 1998;19(1):26–37.

    PubMed  CAS  Google Scholar 

  77. Prueksaritanont T, Subramanian R, Fang X, et al. Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos. 2002;30(5):505–12.

    PubMed  CAS  Google Scholar 

  78. Garcia MJ, Reinoso RF, Sanchez Navarro A, et al. Clinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 2003;25(6):457–81.

    PubMed  CAS  Google Scholar 

  79. 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.

    PubMed  CAS  Google Scholar 

  80. Neuvonen PJ, Backman JT, Niemi M. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin Pharmacokinet. 2008;47(7):463–74.

    PubMed  CAS  Google Scholar 

  81. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141–60.

    PubMed  Google Scholar 

  82. Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). Eur J Clin Pharmacol. 2001;57(5):357–64.

    PubMed  CAS  Google Scholar 

  83. 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(5):584–98.

    PubMed  CAS  Google Scholar 

  84. Martin PD, Warwick MJ, Dane AL, et al. Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers. Clin Ther. 2003;25(10):2553–63.

    PubMed  CAS  Google Scholar 

  85. Keskitalo JE, Zolk O, Fromm MF, et al. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86(2):197–203.

    PubMed  CAS  Google Scholar 

  86. Bellosta S, Corsini A. Statin drug interactions and related adverse reactions. Expert Opin Drug Saf. 2012;11(6):933–46.

    PubMed  CAS  Google Scholar 

  87. 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(1):157–81.

    PubMed  CAS  Google Scholar 

  88. Ieiri I, Higuchi S, Sugiyama Y. Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs. Expert Opin Drug Metab Toxicol. 2009;5(7):703–29.

    PubMed  CAS  Google Scholar 

  89. Niemi M, Pasanen MK, Neuvonen PJ. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin Pharmacol Ther. 2006;80(4):356–66.

    PubMed  CAS  Google Scholar 

  90. Jones HM, Barton HA, Lai Y, et al. Mechanistic pharmacokinetic modeling for the prediction of transporter-mediated disposition in humans from sandwich culture human hepatocyte data. Drug metabolism and disposition: the biological fate of chemicals. 2012;40(5):1007–17.

    CAS  Google Scholar 

  91. Romaine SP, Bailey KM, Hall AS, et al. The influence of SLCO1B1 (OATP1B1) gene polymorphisms on response to statin therapy. Pharmacogenomics J. 2010;10(1):1–11.

    PubMed  CAS  Google Scholar 

  92. Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy—a genomewide study. N Engl J Med. 2008;359(8):789–99.

    PubMed  CAS  Google Scholar 

  93. Ho RH, Tirona RG, Leake BF, et al. Drug and bile acid transporters in rosuvastatin hepatic uptake: function, expression, and pharmacogenetics. Gastroenterology. 2006;130(6):1793–806.

    PubMed  CAS  Google Scholar 

  94. Kopplow K, Letschert K, Konig J, et al. Human hepatobiliary transport of organic anions analyzed by quadruple-transfected cells. Mol Pharmacol. 2005;68(4):1031–8.

    PubMed  CAS  Google Scholar 

  95. Seithel A, Eberl S, Singer K, et al. The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3. Drug Metab Dispos. 2007;35(5):779–86.

    PubMed  CAS  Google Scholar 

  96. Koenen A, Kroemer HK, Grube M, et al. Current understanding of hepatic and intestinal OATP-mediated drug–drug interactions. Expert Rev Clin Pharmacol. 2011;4(6):729–42.

    PubMed  CAS  Google Scholar 

  97. Scripture CD, Pieper JA. Clinical pharmacokinetics of fluvastatin. Clin Pharmacokinet. 2001;40(4):263–81.

    PubMed  CAS  Google Scholar 

  98. Windass AS, Lowes S, Wang Y, et al. The contribution of organic anion transporters OAT1 and OAT3 to the renal uptake of rosuvastatin. J Pharmacol Exp Ther. 2007;322(3):1221–7.

    PubMed  CAS  Google Scholar 

  99. Nishizato Y, Ieiri I, Suzuki H, et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin Pharmacol Ther. 2003;73(6):554–65.

    PubMed  CAS  Google Scholar 

  100. Keskitalo JE, Pasanen MK, Neuvonen PJ, et al. Different effects of the ABCG2 c.421C > A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics. 2009;10(10):1617–24.

    PubMed  CAS  Google Scholar 

  101. Hochman JH, Pudvah N, Qiu J, et al. Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin. Pharm Res. 2004;21(9):1686–91.

    PubMed  CAS  Google Scholar 

  102. Kivisto KT, Niemi M. Influence of drug transporter polymorphisms on pravastatin pharmacokinetics in humans. Pharm Res. 2007;24(2):239–47.

    PubMed  Google Scholar 

  103. Neuvonen PJ. Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics. Curr Opin Investig Drugs. 2010;11(3):323–32.

    PubMed  CAS  Google Scholar 

  104. Thompson MA, Aberg JA, Hoy JF, et al. Antiretroviral treatment of adult HIV infection: 2012 recommendations of the International Antiviral Society-USA panel. JAMA. 2012;308(4):387–402.

    PubMed  CAS  Google Scholar 

  105. Murphy R, Pokrovskiy V, Rozenbaum W, et al. Long-term efficacy and safety of atazanavir (ATV) with stavudine (d4T) and lamivudine (3TC) in patients previously treated with nelfinavir (NFV) or ATV: 108-week results of bms study 008/044. In: 10th conference on retroviruses and opportunistic infections, Boston; 2003.

  106. Martinez-Cajas JL, Wainberg MA. Protease inhibitor resistance in HIV-infected patients: molecular and clinical perspectives. Antiviral Res. 2007;76(3):203–21.

    PubMed  CAS  Google Scholar 

  107. Williams GC, Sinko PJ. Oral absorption of the HIV protease inhibitors: a current update. Adv Drug Deliv Rev. 1999;39(1–3):211–38.

    PubMed  CAS  Google Scholar 

  108. Mouly SJ, Matheny C, Paine MF, et al. Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5. Clin Pharmacol Ther. 2005;78(6):605–18.

    PubMed  CAS  Google Scholar 

  109. Mathias AA, German P, Murray BP, et al. Pharmacokinetics and pharmacodynamics of GS-9350: a novel pharmacokinetic enhancer without anti-HIV activity. Clin Pharmacol Ther. 2009;87(3):322–9.

    PubMed  Google Scholar 

  110. Tozzi V. Pharmacogenetics of antiretrovirals. Antiviral Res. 2010;85(1):190–200.

    PubMed  CAS  Google Scholar 

  111. Shah BM, Schafer JJ, Priano J, et al. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2013. doi:10.1002/phar.1237.

  112. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer for atazanavir plus emtricitabine/tenofovir DF in treatment-naive HIV-1-infected patients: Week 48 results. J Infect Dis 2013;PMID:23532097.

    Google Scholar 

  113. Permpalung N, Putcharoen O, Avihingsanon A, et al. Treatment of HIV infection with once-daily regimens. Expert Opin Pharmacother. 2012;13(16):2301–17.

    PubMed  CAS  Google Scholar 

  114. Kis O, Robillard K, Chan GN, et al. The complexities of antiretroviral drug–drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci. 2009;31(1):22–35.

    PubMed  Google Scholar 

  115. Cressey TR, Lallemant M. Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: an update. Infect Genet Evol. 2007;7(2):333–42.

    PubMed  CAS  Google Scholar 

  116. Minuesa G, Huber-Ruano I, Pastor-Anglada M, et al. Drug uptake transporters in antiretroviral therapy. Pharmacol Ther. 2011;132(3):268–79.

    PubMed  CAS  Google Scholar 

  117. Olin JL, Spooner LM, Klibanov OM. Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single tablet for HIV-1 infection treatment. Ann Pharmacother. 2012;46(12):1671–7.

    PubMed  Google Scholar 

  118. Ferenci P, Reddy KR. Impact of HCV protease-inhibitor-based triple therapy for chronic HCV genotype 1 infection. Antivir Ther. 2011;16(8):1187–201.

    PubMed  CAS  Google Scholar 

  119. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(4):1433–44.

    PubMed  Google Scholar 

  120. Jacobson IM, Pawlotsky JM, Afdhal NH, et al. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat. 2012;19(Suppl 2):1–26.

    PubMed  Google Scholar 

  121. Burger D, Back D, Buggisch P, et al. Clinical management of drug–drug interactions in HCV therapy: Challenges and solutions. J Hepatol. 2012. doi:10.1016/j.jhep.2012.10.027.

  122. Hare CB, Vu MP, Grunfeld C, et al. Simvastatin-nelfinavir interaction implicated in rhabdomyolysis and death. Clin Infect Dis. 2002;35(10):e111–2.

    PubMed  Google Scholar 

  123. Hsyu PH, Schultz-Smith MD, Lillibridge JH, et al. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother. 2001;45(12):3445–50.

    PubMed  CAS  Google Scholar 

  124. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, et al. Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers: ACTG Study A5047. AIDS. 2002;16(4):569–77.

    PubMed  CAS  Google Scholar 

  125. Granfors MT, Wang JS, Kajosaari LI, et al. Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol. 2006;98(1):79–85.

    PubMed  CAS  Google Scholar 

  126. Cheng CH, Miller C, Lowe C, et al. Rhabdomyolysis due to probable interaction between simvastatin and ritonavir. Am J Health Syst Pharm. 2002;59(8):728–30.

    PubMed  Google Scholar 

  127. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet. 2002;41(14):1195–211.

    PubMed  CAS  Google Scholar 

  128. Schmidt GA, Hoehns JD, Purcell JL, et al. Severe rhabdomyolysis and acute renal failure secondary to concomitant use of simvastatin, amiodarone, and atazanavir. J Am Board Fam Med. 2007;20(4):411–6.

    PubMed  Google Scholar 

  129. FDA, Important information about interactions between certains hepatitis C drugs and cholesterol-lowering statin drugs. 2012. Available from http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm294485.htm. Accessed 18 Apr 2013.

  130. Mah Ming JB, Gill MJ. Drug-induced rhabdomyolysis after concomitant use of clarithromycin, atorvastatin, and lopinavir/ritonavir in a patient with HIV. AIDS Patient Care STDS. 2003;17(5):207–10.

    PubMed  Google Scholar 

  131. Product Information: LEXIVA(R) oral tablets, oral suspension, fosamprenavir calcium oral tablets, oral suspension. ViiV Healthcare and Vertex Pharmaceuticals Incorporated (per FDA), Research Triangle Park, NC. 2012.

  132. Pham PA, la Porte CJ, Lee LS, et al. Differential effects of tipranavir plus ritonavir on atorvastatin or rosuvastatin pharmacokinetics in healthy volunteers. Antimicrob Agents Chemother. 2009;53(10):4385–92.

    PubMed  CAS  Google Scholar 

  133. Information Product. LIPITOR(R) oral tablets, atorvastatin calcium oral tablets. New York: Pfizer (Per FDA); 2012.

    Google Scholar 

  134. Information Product. PREZISTA(R) oral suspension, oral film coated tablets, darunavir oral suspension, oral film coated tablets. Titusville: Janssen Therapeutics (per manufacturer); 2012.

    Google Scholar 

  135. Lee JE, van Heeswijk R, Alves K, et al. Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. Antimicrob Agents Chemother. 2011;55(10):4569–74.

    PubMed  CAS  Google Scholar 

  136. Product Information: VICTRELIS(R) oral capsules, boceprevir oral capsules. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station. 2012.

  137. Busti AJ, Bain AM, Hall RG 2nd, et al. Effects of atazanavir/ritonavir or fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. J Cardiovasc Pharmacol. 2008;51(6):605–10.

    PubMed  CAS  Google Scholar 

  138. Kiser JJ, Gerber JG, Predhomme JA, et al. Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir Immune Defic Syndr. 1999;47(5):570–8.

    Google Scholar 

  139. van der Lee M, Sankatsing R, Schippers E, et al. Pharmacokinetics and pharmacodynamics of combined use of lopinavir/ritonavir and rosuvastatin in HIV-infected patients. Antivir Ther. 2007;12(7):1127–32.

    PubMed  Google Scholar 

  140. de Kanter CT, Keuter M, van der Lee MJ, et al. Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir. Antivir Ther. 2011;16(3):435–7.

    PubMed  Google Scholar 

  141. Tse FL, Jaffe JM, Troendle A. Pharmacokinetics of fluvastatin after single and multiple doses in normal volunteers. J Clin Pharmacol. 1992;32(7):630–8.

    PubMed  CAS  Google Scholar 

  142. Product Information: APTIVUS(R) oral capsules, solution, tipranavir oral capsules, solution. Boehringer Ingelheim Pharmaceuticals, Inc. (per manufacturer), Ridgefield, CT. 2012.

  143. Product Information: VIRACEPT(R) oral tablets, oral powder, nelfinavir mesylate oral tablets, oral powder. ViiV Healthcare Company (Per FDA), Research Triangle Park, NC. 2012.

  144. Aberg JA, Rosenkranz SL, Fichtenbaum CJ, et al. Pharmacokinetic interaction between nelfinavir and pravastatin in HIV-seronegative volunteers: ACTG Study A5108. AIDS. 2006;20(5):725–9.

    PubMed  CAS  Google Scholar 

  145. Aquilante CL, Kiser JJ, Anderson PL, et al. Influence of SLCO1B1 polymorphisms on the drug–drug interaction between darunavir/ritonavir and pravastatin. J Clin Pharmacol. 2012;52(11):1725–38.

    PubMed  CAS  Google Scholar 

  146. Product Information: LIVALO(R) oral tablets, pitavastatin oral tablets. Kowa Pharmaceuticals America, Inc. and Lilly USA, LLC (per FDA), Montgomery, AL, 2012.

  147. Pham PA, Lee L, Fuchs E, et al. Pharmacokinetic interaction between tipranavir/ritonavir and rosuvastatin (Poster 767). In: 13th Conference on Retroviruses and Opportunistic Infections. Boston, 2008.

  148. Fichtenbaum CJ, Samineni D, Moore E, et al. Darunavir/ritonavir (DRV/rtv) increases rosuvastatin (RSV) concentrations but does not alter lipid-lowering effect in healthy volunteers (Abstract no. WEPE0101). In: XVIII international AIDS conference, Vienna, Austria; 2010.

  149. Carr R, Andre A, Bertz R, et al. Concomitant administration of ABT-378/ritonavir (ABT-378/r) results in a clinically important pharmacokinetic (PK) interaction with atorvastatin (ATO) but not pravastatin (PRA). (Abstract 1644). In: 40th ICAAC, Toronto, Canada; 2000.

  150. Wire M, Baker K, Moore K, et al. The Pharmacokinetic (PK) Interaction of GW433908 (908) with Atorvastatin (ATO) and 908/ Ritonavir (RTV) with ATO (APV10013) (abstract A-1622) 43rd ICAAC, 2003; Chicago.

  151. Aslangul E, Assoumou L, Bittar R, et al. Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial. Aids. 2010;24(1):77–83.

    PubMed  CAS  Google Scholar 

  152. Bittar R, Giral P, Aslangul E, et al. Effects of rosuvastatin versus pravastatin on low-density lipoprotein diameter in HIV-1-infected patients receiving ritonavir-boosted protease inhibitor. Aids. 2012;26(14):1801–5.

    PubMed  CAS  Google Scholar 

  153. Hayashi T, Yokote K, Saito Y, et al. Pitavastatin: efficacy and safety in intensive lipid lowering. Expert Opin Pharmacother. 2007;8(14):2315–27.

    PubMed  CAS  Google Scholar 

  154. Mukhtar RY, Reid J, Reckless JP. Pitavastatin. Int J Clin Pract. 2005;59(2):239–52.

    PubMed  CAS  Google Scholar 

  155. Fung HB, Kirschenbaum HL, Hameed R. Amprenavir: a new human immunodeficiency virus type 1 protease inhibitor. Clin Ther. 2000;22(5):549–72.

    PubMed  CAS  Google Scholar 

  156. Information Product. REYATAZ(R) oral capsules, atazanavir sulfate oral capsules. Princeton: Bristol-Myers Squibb Company; 2011.

    Google Scholar 

  157. FDA. Consumer Health Information: FDA Expands Advice on Statin Risks. 2012 09-08 [cited 2013-01-11]; http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm293330.htm.

  158. Product Information: CRIXIVAN(R) oral capsules, indinavir sulfate oral capsules. Merck Sharp & Dohme Corp. (per FDA), Whitehouse Station. 2012.

  159. Information Product. KALETRA(R) film coated oral tablets, oral solution, lopinavir and ritonavir film coated oral tablets, oral solution. North Chicago: Abbott Laboratories; 2009.

    Google Scholar 

  160. Williams P, Muirhead G, Madigan M. Disposition and bioavailability of the HIV-proteinase inhibitor, Ro 31-8959, after single oral doses in healthy volunteers. Br J Clin Pharmacol. 1992;34:155P–6P.

    Google Scholar 

  161. Information Product. INVIRASE(R), saquinavir oral capsules and tablets. Nutley: Roche Laboratories Inc.; 2005.

    Google Scholar 

  162. Information Product. NORVIR(R) oral capsules, solution, ritonavir oral capsules, solution. North Chicago: Abbott Laboratories; 2008.

    Google Scholar 

  163. Product Information: STRIBILD(TM) oral tablets, elvitegravir cobicistat emtricitabine tenofovir disoproxil fumarate oral tablets. Gilead Sciences, Inc. (per manufacturer), Foster City. 2012.

  164. Information Product. INCIVEK(TM) film coated oral tablets, telaprevir film coated oral tablets. Cambridge: Vertex Pharmaceuticals Incorporated; 2011.

    Google Scholar 

  165. Hoetelmans R, Lasure A, Koester A. The effect of TMC114, a potent next-generation HIV protease inhibitor, with low-dose ritonavir on atorvastatin pharmacokinetics (poster H-865). ICAAC, Washington, DC; 2004.

  166. Hulskotte E, Gupta S, Xuan F, et al. Pharmacokinetic evaluation of the interaction between the HCV protease inhibitor boceprevir and the HMG-CoA reductase inhibitors atorvastatin and pravastatin. HEP DART, Koloa, Hawaii; 2011.

  167. Sekar V, Spinosa-Guzman S, Marien K. Pharmacokinetic drug–drug interaction between the new HIV protease inhibitor darunavir (TMC114) and the lipid-lowering agent pravastatin (Abstract 55). In: 8th International Workshop on Pharmacology of HIV Therapy, 2007; Budapest.

Download references

Author information

Authors and Affiliations

  1. Clinical Pharmacy Department, Assistance Publique Hôpitaux de Paris, Hôpital Bicêtre, Hôpitaux Universitaires Paris Sud AP/HP, 78 rue du Général Leclerc, 94270, Kremlin Bicêtre, France

    Benoit Chauvin, Sylvain Drouot, Aurélie Barrail-Tran & Anne-Marie Taburet

  2. Clinical Pharmacy and Pharmacokinetics Department, Faculty of Pharmacy, University of Paris-Sud, Chatenay-Malabry, France

    Aurélie Barrail-Tran

Authors
  1. Benoit Chauvin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sylvain Drouot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aurélie Barrail-Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne-Marie Taburet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne-Marie Taburet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chauvin, B., Drouot, S., Barrail-Tran, A. et al. Drug–Drug Interactions Between HMG-CoA Reductase Inhibitors (Statins) and Antiviral Protease Inhibitors. Clin Pharmacokinet 52, 815–831 (2013). https://doi.org/10.1007/s40262-013-0075-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-013-0075-4

Keywords

Search

Navigation