Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist
First Online: 22 December 2011 Received: 20 September 2011 Accepted: 01 December 2011 DOI:
Cite this article as: Bruderer, S., Äänismaa, P., Homery, M. et al. AAPS J (2012) 14: 68. doi:10.1208/s12248-011-9316-3 Abstract
Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition,
in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration–time profiles during a dose interval (AUC τ) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC τ of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC τ between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent. KEY WORDS cyclosporine (Cs) endothelin macitentan pharmacokinetics rifampin REFERENCES
Iglarz M, Binkert C, Morrison K, Fischli W, Gatfield J, Treiber A,
. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008;327(3):736–45.
Sidharta PN, van Giersbergen PL, Halabi A, Dingemanse J. Macitentan: entry-into-humans study with a new endothelin receptor antagonist. Eur J Clin Pharmacol. 2011;67(10):977–84.
Bruderer S, Sidharta P, Dingemanse J. Pharmacokinetics, tolerability, and safety of the dual endothelin receptor antagonist macitentan in Japanese and Caucasian healthy subjects. Clin Pharmacol Ther. 2011;89 Suppl 1:83.
Kummer O, Haschke M, Hammann F, Bodmer M, Bruderer S, Regnault Y,
. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan. Eur J Pharm Sci. 2009;38(4):384–8.
Kim RB. Organic anion-transporting polypeptide (OATP) transporter family and drug disposition. Eur J Clin Invest. 2003;33(2):1–5.
International Transporter Consortium. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.
Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampin: clinical relevance. Clin Pharmacokinet. 2003;42(9):819–50.
Vavricka SR, Van Montfoort J, Ha HR, Meier PJ, Fattinger K. Interactions of rifamycin SV and rifampin with organic anion uptake systems of human liver. Hepatology. 2002;36(1):164–72.
Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin and rifabutin drug interactions. Am J Sci. 2008;335(2):126–36.
Sidharta PN, Atsmon J, Dingemanse J. Investigation of the effect of ketoconazole on the pharmacokinetics of macitentan in healthy male subjects. Br J Clin Pharmacol. 2010;70:730–1. Abstract.
van Giersbergen PLM, Bodin F, Dingemanse J. Cyclosporin increases the exposure to tezosentan, an intravenous dual endothelin receptor antagonist. Eur J Clin Pharmacol. 2002;58(4):243–5.
Binet I, Wallnöfer A, Weber C, Jones R, Thiel G. Renal hemodynamics and pharmaco-kinetics of bosentan with and without CsA. Kidney Int. 2000;57(1):224–31.
Novartis. Neoral, summary of product characteristics of Cs. 2009.
Sanofi-aventis. Rifadin, summary of product characteristics of rifampin. 2009.
U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Draft guidance for industry, drug interaction studies–study design, data analysis, and implications for dosing and labeling. 2006.
Sidharta PN, Dingemanse J. Multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist ACT-064992 in healthy human subjects. (Abstract). J Clin Pharmacol. 2008;48:1114.
Treiber A, Schneiter R, Häuser S, Stieger B. Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampin, and sildenafil. Drug Metab Dispos. 2007;35(8):1400–07.
Actelion Pharmaceuticals Ltd. Tracleer (bosentan) tablets. United States Food and Drug Administration Drug Product Label 2009.
Spence R, Mandagere A, Richards DB, Magee MH, Dufton C, Boinpally R. Potential for pharmacokinetic interactions between ambrisentan and cyclosporine. Clin Pharmacol Ther. 2010;88(4):513–20.
Kon V, Sugiura M, Inagami T, Harvie BR, Ichikawa I, Hoover RL. Role of endothelin in cyclosporine-induced glomerular dysfunction. Kidney Int. 1990;37(6):1487–91.
Perico N, Dadan J, Remuzzi G. Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat. J Am Soc Nephrol. 1990;1(1):76–83.
Fogo A, Hellings SE, Inagami T, Kon V. Endothelin receptor antagonism is protective in
acute cyclosporine toxicity. Kidney Int. 1992;42(3):770–4.
van Giersbergen PLM, Treiber A, Schneiter R, Dietrich H, Dingemanse J. Inhibitory and inductive effects of rifampin on the pharmacokinetics of bosentan in healthy subjects. Clin Pharmacol Ther. 2007;81(3):414–9.
Harrison B, Magee MH, Mandagere A, Walker G, Dufton C, Henderson LS, Boinpally R. Effects of rifampin (rifampin) on the pharmacokinetics and safety of ambrisentan in healthy subjects: a single-sequence, open-label study. Clin Drug Investig. 2010;30(12):875–85.
Xiong H, Carr RA, Locke CS, Katz DA, Achari R, Doan TT,
. Dual effects of rifampin on the pharmacokinetics of atrasentan. J Clin Pharmacol. 2007;47(4):423–9.
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(1):78–85.
Bruderer S, Hopfgartner G, Seiberling M, Wank J, Sidharta P, Treiber A, Dingemanse J. Allschwil: Actelion Pharmaceuticals Ltd. 2011. (Data on file)
US Food and Drug Administration. Guidance for industry 2008, safety testing of drug metabolites. US Department of Health and Human Services. Food and Drug Administration, Center for Drug Evaluation and Research (CDER). February 2008. Pharmacology and Toxicology.
US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry M3(R2) 2010, nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. 2010 (Revision 1).