Metabolism and disposition of [14C]BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor, after oral administration to humans.
(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.
Christopher
Lisa J
LJ
Departments of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08543, USA. lisa.christopher@bms.com
Hong
Haizheng
H
Vakkalagadda
Blisse J
BJ
Clemens
Pamela L
PL
Su
Hong
H
Roongta
Vikram
V
Allentoff
Alban
A
Sun
Haojun
H
Heller
Kevin
K
Harbison
Christopher T
CT
Iyer
Ramaswamy A
RA
Humphreys
William G
WG
Wong
Tai
T
Zhang
Steven
S
D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008297:Male; D010084:Oxidation-Reduction; D010880:Piperidines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000378:metabolism; D011758:Pyrroles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014227:Triazines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000652:urine; D055815:Young Adult; D000099148:UGT1A1 Enzyme
D000970:Antineoplastic Agents; D019389:Cytochrome P-450 CYP2D6; D020719:Glucuronides; D014453:Glucuronosyltransferase; D010880:Piperidines; D011494:Protein Kinases; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D014227:Triazines; D000099148:UGT1A1 Enzyme; C552150:BMS-690514