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Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin

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Summary

GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23 % and the area under the curve (AUC) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions.

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Acknowledgments

The authors would like to recognize the bioanalytical, technical and clinical support services provided by Celerion, USA; Covance, USA; and inVentive, Canada; as well as the in house bioanalytical and statistics support provided by Susan Ohorodnik and Michael Hancock, respectively, of GTx Inc., USA. Manuscript preparation supported by Robert Wills, Mary Ann Johnston and Michael Mohler who are all current stock holders and employees of GTx Inc. Funding for these studies was provided by GTx, Inc. The authors are all former GTx employees and J Dalton receives royalties through the University of Tennessee Research Foundation as an inventor of GTx-024 and is a paid consultant to GTx, Inc.

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Correspondence to James T. Dalton.

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Funding

These studies were funded by GTx, Inc.

Robert Wills Ph. D., Mary-Ann Johnston PharmD, and Michael Mohler PharmD, Ph.D. are all employees of GTx Inc. and provided assistance with manuscript preparation.

Open access publication of this manuscript was sponsored by drug company GTx, Inc.

Conflict of interest

Drs. Coss, Jones and Dalton are all former employees of GTx, Inc. Drs. Jones and Dalton are GTx-024 inventors. Dr. Dalton receives royalties through the University of Tennessee Research Foundation as an inventor of GTx-024 and is a paid consultant to GTx, Inc. The views expressed do not represent the views of the Agency or the United States.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.

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Coss, C.C., Jones, A. & Dalton, J.T. Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin. Invest New Drugs 34, 458–467 (2016). https://doi.org/10.1007/s10637-016-0353-8

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  • DOI: https://doi.org/10.1007/s10637-016-0353-8

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