The effects on metabolic clearance when administering a potent CYP3A autoinducer with the prototypic CYP3A inhibitor, ketoconazole.
Ketoconazole is recognized as the prototypical CYP3A inhibitor and is often used to determine the metabolic CYP3A liabilities of new chemical entities in preclinical and clinical studies. Ketoconazole has been commercially available for approximately 30 years and was marketed before drug-metabolizing enzymes were well characterized; consequently, little is known about its metabolic profile. Semagacestat, a γ-secretase inhibitor investigated as a potential therapy for Alzheimer's disease, was determined to be a potent CYP3A autoinducer in human hepatocytes. Two human studies were conducted to assess the induction potential of semagacestat. In the first study (study 1, n = 20), semagacestat increased the mean apparent clearance (CL/F) of oral midazolam (76-324 l/h) and nifedipine (63-229 l/h) as predicted from hepatocytes. In a second (steady-state) study (study 2, n = 20), semagacestat CL/F increased from 22 after a single dose to 31 l/h. Ketoconazole decreased semagacestat CL/F by 32% after a single dose of semagacestat [geometric means ratio estimate, 0.68; 90% confidence interval (CI). 0.64, 0.73] and 46% at steady state (geometric means ratio estimate. 0.54; 90% CI, 0.51, 0.58). Ketoconazole area under the concentration-time curve over 8 h decreased 49% from first to last day of semagacestat dosing. Semagacestat significantly increases the oral clearance of CYP3A substrates, confirming its inducer designation. More importantly, when administered with a potent CYP3A inducer at steady state, ketoconazole's plasma exposure decreased, indicating that it may also be cleared by CYP3A, other inducible enzymes or transporters, or both.
Eli Lilly and Company, Indianapolis, IN, USA. mayan@lilly.com
Mosun A
MA
Ayan-Oshodi
Brian A
BA
Willis
William F
WF
Annes
Stephen L
SL
Lowe
Stuart
S
Friedrich
Amparo
A
de la Peña
Wei
W
Zhang
Thomas
T
Brown
Stephen D
SD
Wise
Stephen D
SD
Hall
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D019540:Area Under Curve; D001381:Azepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006900:Hydroxylation; D007654:Ketoconazole / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D008954:Models, Biological; D009543:Nifedipine / Q000008:administration & dosage / Q000493:pharmacokinetics; D013739:Testosterone / Q000378:metabolism; D055815:Young Adult
D001381:Azepines; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C484278:N2-((2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl)-N1-((7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-L-alaninamide; D013739:Testosterone; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D053829:Amyloid Precursor Protein Secretases; D009543:Nifedipine; D000409:Alanine; D008874:Midazolam; D007654:Ketoconazole