Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters in vitro and assess its importance for pharmacokinetics in vivo Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. In vivo experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.

Charles University Faculty of Pharmacy in Hradec Kralove Department of Pharmacology and Toxicology Hradec Kralove Czech Republic

Zobrazit více v PubMed

European Medicines Agency. Edurant 25 mg film-coated tablets: summary of product characteristics. European Medicines Agency, London, United Kingdom: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002264/WC500118874.pdf Accessed 21 April 2016.

Center for Drug Evaluation and Research. Clinical pharmacology and biopharmaceutics review(s), application number 202022Orig1s000. U.S. Food and Drug Administration, Washington, DC: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/202022Orig1s000ClinPharmR.pdf Accessed 21 April 2016.

Azijn H, Tirry I, Vingerhoets J, de Bethune MP, Kraus G, Boven K, Jochmans D, Van Craenenbroeck E, Picchio G, Rimsky LT. 2010. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother 54:718–727. doi:10.1128/AAC.00986-09. PubMed DOI PMC

Goebel F, Yakovlev A, Pozniak AL, Vinogradova E, Boogaerts G, Hoetelmans R, de Bethune MPP, Peeters M, Woodfall B. 2006. Short-term antiviral activity of TMC278–a novel NNRTI–in treatment-naive HIV-1-infected subjects. AIDS 20:1721–1726. doi:10.1097/01.aids.0000242818.65215.bd. PubMed DOI

Panel on Antiretroviral Guidelines for Adults and Adolescents. 2016. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services, Washington, DC. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf Accessed 20 November 2016.

Kis O, Robillard K, Chan GN, Bendayan R. 2010. The complexities of antiretroviral drug-drug interactions: role of ABC and SLC transporters. Trends Pharmacol Sci 31:22–35. doi:10.1016/j.tips.2009.10.001. PubMed DOI

Neumanova Z, Cerveny L, Greenwood SL, Ceckova M, Staud F. 2015. Effect of drug efflux transporters on placental transport of antiretroviral agent abacavir. Reprod Toxicol 57:176–182. doi:10.1016/j.reprotox.2015.07.070. PubMed DOI

Neumanova Z, Cerveny L, Ceckova M, Staud F. 2015. Role of ABCB1, ABCG2, ABCC2 and ABCC5 transporters in placental passage of zidovudine. Biopharm Drug Dispos 37:28–38. doi:10.1002/bdd.1993. PubMed DOI

Reznicek J, Ceckova M, Cerveny L, Muller F, Staud F. 2016. Emtricitabine is a substrate of MATE1 but not of OCT1, OCT2, P-gp, BCRP or MRP2 transporters. Xenobiotica 47:77–85. doi:10.3109/00498254.2016.1158886. PubMed DOI

Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. 1987. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A 84:7735–7738. doi:10.1073/pnas.84.21.7735. PubMed DOI PMC

Roninson IB, Chin JE, Choi K, Gros P, Housman DE, Fojo A, Shen D, Gottesman MM, Pastan I. 1986. Isolation of human Mdr-DNA sequences amplified in multidrug-resistant Kb carcinoma cells. Proc Natl Acad Sci U S A 83:4538–4542. doi:10.1073/pnas.83.12.4538. PubMed DOI PMC

Doyle LA, Ross DD. 2003. Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22:7340–7358. doi:10.1038/sj.onc.1206938. PubMed DOI

Konig J, Nies AT, Cui YH, Leier I, Keppler D. 1999. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta Biomembr 1461:377–394. doi:10.1016/S0005-2736(99)00169-8. PubMed DOI

Chan LM, Lowes S, Hirst BH. 2004. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 21:25–51. doi:10.1016/j.ejps.2003.07.003. PubMed DOI

Lee G, Dallas S, Hong M, Bendayan R. 2001. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol Rev 53:569–596. doi:10.1146/annurev.pharmtox.41.1.569. PubMed DOI

Lee W, Kim RB. 2004. Transporters and renal drug elimination. Annu Rev Pharmacol Toxicol 44:137–166. doi:10.1146/annurev.pharmtox.44.101802.121856. PubMed DOI

Bart J, Hollema H, Groen HJ, de Vries EG, Hendrikse NH, Sleijfer DT, Wegman TD, Vaalburg W, van der Graaf WT. 2004. The distribution of drug-efflux pumps, P-gp, BCRP, MRP1 and MRP2, in the normal blood-testis barrier and in primary testicular tumours. Eur J Cancer 40:2064–2070. doi:10.1016/j.ejca.2004.05.010. PubMed DOI

Koepsell H, Lips K, Volk C. 2007. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251. doi:10.1007/s11095-007-9254-z. PubMed DOI

Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H. 1997. Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881. doi:10.1089/dna.1997.16.871. PubMed DOI

Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, Inui K. 2002. Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13:866–874. PubMed

Motohashi H, Inui K. 2013. Organic cation transporter OCTs (SLC22) and MATEs (SLC47) in the human kidney. AAPS J 15:581–588. doi:10.1208/s12248-013-9465-7. PubMed DOI PMC

FDA. 2012. Guidance for industry, drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. Clinical Pharmacology. FDA, Silver Spring, MD. PubMed

Zamek-Gliszczynski MJ, Hoffmaster KA, Tweedie DJ, Giacomini KM, Hillgren KM. 2012. Highlights from the International Transporter Consortium Second Workshop. Clin Pharmacol Ther 92:553–556. doi:10.1038/clpt.2012.126. PubMed DOI

Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. 2010. Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236. doi:10.1038/nrd3028. PubMed DOI PMC

Zhang L, Zhang YD, Zhao P, Huang SM. 2009. Predicting drug-drug interactions: an FDA perspective. AAPS J 11:300–306. doi:10.1208/s12248-009-9106-3. PubMed DOI PMC

EMA. 2012. Guideline on the investigation of drug interactions. European Medicines Agency, London, United Kingdom.

Weiss J, Haefeli WE. 2013. Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro. Int J Antimicrobial Agents 41:484–487. doi:10.1016/j.ijantimicag.2013.01.004. PubMed DOI

Moss DM, Liptrott NJ, Curley P, Siccardi M, Back DJ, Owen A. 2013. Rilpivirine inhibits drug transporters ABCB1, SLC22A1, and SLC22A2 in vitro. Antimicrob Agents Chemother 57:5612–5618. doi:10.1128/AAC.01421-13. PubMed DOI PMC

Cohen CJ, Molina JM, Cassetti I, Chetchotisakd P, Lazzarin A, Orkin C, Rhame F, Stellbrink HJ, Li T, Crauwels H, Rimsky L, Vanveggel S, Williams P, Boven K, ECHO, THRIVE Study Groups. 2013. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two phase III randomized trials. AIDS 27:939–950. doi:10.1097/QAD.0b013e32835cee6e. PubMed DOI

Curran A, Rojas J, Cabello A, Troya J, Imaz A, Domingo P, Martinez E, Ryan P, Gorgolas M, Podzamczer D, Knobel H, Gutierrez F, Ribera E. 2016. Effectiveness and safety of an abacavir/lamivudine + rilpivirine regimen for the treatment of HIV-1 infection in naive patients. J Antimicrob Chemother 71:3510–3514. doi:10.1093/jac/dkw347. PubMed DOI

Palacios R, Perez-Hernandez IA, Martinez MA, Mayorga ML, Gonzalez-Domenech CM, Omar M, Olalla J, Romero A, Romero JM, Perez-Camacho I, Hernandez-Quero J, Santos J. 2016. Efficacy and safety of switching to abacavir/lamivudine (ABC/3TC) plus rilpivirine (RPV) in virologically suppressed HIV-infected patients on HAART. Eur J Clin Microbiol Infect Dis 35:815–819. doi:10.1007/s10096-016-2602-3. PubMed DOI

Troya J, Ryan P, Ribera E, Podzamczer D, Hontanon V, Terron JA, Boix V, Moreno S, Barrufet P, Castano M, Carrero A, Galindo MJ, Suarez-Lozano I, Knobel H, Raffo M, Solis J, Yllescas M, Esteban H, Gonzalez-Garcia J, Berenguer J, Imaz A, GESIDA-8314 Study Group. 2016. Abacavir/lamivudine plus rilpivirine is an effective and safe strategy for HIV-1 suppressed patients: 48 week results of the SIMRIKI retrospective study. PLoS One 11:e0164455. doi:10.1371/journal.pone.0164455. PubMed DOI PMC

Ceckova M, Reznicek J, Ptackova Z, Cerveny L, Muller F, Kacerovsky M, Fromm MF, Glazier JD, Staud F. 2016. Role of ABC and solute carrier transporters in the placental transport of lamivudine. Antimicrob Agents Chemother 60:5563–5572. doi:10.1128/AAC.00648-16. PubMed DOI PMC

Müller F, König J, Hoier E, Mandery K, Fromm MF. 2013. Role of organic cation transporter OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2-K for transport and drug interactions of the antiviral lamivudine. Biochem Pharmacol 86:808–815. doi:10.1016/j.bcp.2013.07.008. PubMed DOI

Cihalova D, Hofman J, Ceckova M, Staud F. 2013. Purvalanol A, olomoucine II and roscovitine inhibit ABCB1 transporter and synergistically potentiate cytotoxic effects of daunorubicin in vitro. PLoS One 8:e83467. doi:10.1371/journal.pone.0083467. PubMed DOI PMC

Ceckova M, Libra A, Pavek P, Nachtigal P, Brabec M, Fuchs R, Staud F. 2006. Expression and functional activity of breast cancer resistance protein (BCRP, ABCG2) transporter in the human choriocarcinoma cell line bewo. Clin Exp Pharmacol Physiol 33:58–65. doi:10.1111/j.1440-1681.2006.04324.x. PubMed DOI

Zhang L, Zhang YD, Strong JM, Reynolds KS, Huang SM. 2008. A regulatory viewpoint on transporter-based drug interactions. Xenobiotica 38:709–724. doi:10.1080/00498250802017715. PubMed DOI

Taipalensuu J, Tornblom H, Lindberg G, Einarsson C, Sjoqvist F, Melhus H, Garberg P, Sjostrom B, Lundgren B, Artursson P. 2001. Correlation of gene expression of ten drug efflux proteins of the ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. J Pharmacol Exp Ther 299:164–170. PubMed

Brown KC, Paul S, Kashuba AD. 2009. Drug interactions with new and investigational antiretrovirals. Clin Pharmacokinet 48:211–241. doi:10.2165/00003088-200948040-00001. PubMed DOI PMC

Han HK. 2011. Role of transporters in drug interactions. Arch Pharm Res 34:1865–1877. doi:10.1007/s12272-011-1107-y. PubMed DOI

König J, Müller F, Fromm MF. 2013. Transporters and drug-drug interactions: important determinants of drug disposition and effects. Pharmacol Rev 65:944–966. doi:10.1124/pr.113.007518. PubMed DOI

Müller F, Fromm MF. 2011. Transporter-mediated drug-drug interactions. Pharmacogenomics 12:1017–1037. PubMed

Langmann T, Mauerer R, Zahn A, Moehle C, Probst M, Stremmel W, Schmitz G. 2003. Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues. Clin Chem 49:230–238. PubMed

Shapiro AB, Ling V. 1998. The mechanism of ATP-dependent multidrug transport by P-glycoprotein. Acta Physiol Scand 163:227–234. PubMed

Mittra R, Pavy M, Subramanian N, George AM, O'Mara ML, Kerr ID, Callaghan R. 2016. Location of contact residues in pharmacologically distinct drug binding sites on P-glycoprotein. Biochem Pharmacol doi:10.1016/j.bcp.2016.10.002. PubMed DOI

Garvey L, Winston A. 2009. Rilpivirine: a novel non-nucleoside reverse transcriptase inhibitor. Expert Opin Investig Drugs 18:1035–1041. doi:10.1517/13543780903055056. PubMed DOI

Sharma M, Saravolatz LD. 2013. Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor. J Antimicrob Chemother 68:250–256. doi:10.1093/jac/dks404. PubMed DOI

Crauwels H, van Heeswijk RPG, Stevens M, Buelens A, Vanveggel S, Boven K, Hoetelmans R. 2013. Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AIDS Rev 15:87–101. PubMed

National Research Council. 1996. Guide for the care and use of laboratory animals. National Academies Press, Washington, DC: http://www.ncbi.nlm.nih.gov/books/NBK54050.

Council of Europe. 1986. European convention for the protection of vertebrate animals used for experimental and other scientific purposes. European treaty series no. 123. Council of Europe, Strasbourg, France.

Tong L, Phan TK, Robinson KL, Babusis D, Strab R, Bhoopathy S, Hidalgo IJ, Rhodes GR, Ray AS. 2007. Effects of human immunodeficiency virus protease inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob Agents Chemother 51:3498–3504. doi:10.1128/AAC.00671-07. PubMed DOI PMC

Anti-HIV and Anti-Hepatitis C Virus Drugs Inhibit P-Glycoprotein Efflux Activity in Caco-2 Cells and Precision-Cut Rat and Human Intestinal Slices