Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin.
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.
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Christopher C
CC
Coss
Division of Bioequivalence, Office of Generic Drugs, United States Food and Drug Administration, Silver Spring, MD, USA.
Amanda
A
Jones
Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St, Ann Arbor, MI, 48109-1065, USA. daltonjt@umich.edu.
James T
JT
Dalton
D000328:Adult; D000813:Anilides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D000068579:Celecoxib / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D020719:Glucuronides / Q000097:blood; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011339:Probenecid / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium / Q000493:pharmacokinetics / Q000494:pharmacology*; D055815:Young Adult
C410798:AR protein, human; D000813:Anilides; D020719:Glucuronides; D011944:Receptors, Androgen; D017964:Itraconazole; D000068718:Rosuvastatin Calcium; D003577:Cytochrome P-450 Enzyme System; D000068579:Celecoxib; C547106:ostarine; D011339:Probenecid; D012293:Rifampin
DDI; Drug drug interaction; Enobosarm; GTx-024; SARM; Selective androgen receptor modulator