title: Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [(13) C8 ]-evacetrapib as a tracer.
abstract: This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated. Bioavailability was calculated as the ratio of least-squares geometric mean of dose-normalized AUC (oral : IV) and corresponding 90% confidence interval (CI). Bioavailability of evacetrapib was 44.8% (90% CI: 42.2-47.6%) for AUC(0-∞) and 44.3% (90% CI: 41.8-46.9%) for AUC(0-tlast ). Evacetrapib was well tolerated with no reports of clinically significant safety assessment findings. This is among the first studies to estimate absolute bioavailability using simultaneous administration of an unlabeled oral dose with a (13) C-labeled IV microdose tracer at about 1/1000(th) the oral dose, with measurement in the pg/mL range. This approach is beneficial for poorly soluble drugs, does not require additional toxicology studies, does not change oral dose pharmacokinetics, and ultimately gives researchers another tool to evaluate absolute bioavailability.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Ellen A
authors.initials: EA
authors.lastname: Cannady
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Aktham
authors.initials: A
authors.lastname: Aburub
authors.affiliation: Clinical Operations, Covance Inc., Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Ward
authors.affiliation: Covance Laboratories Ltd., Covance Inc., Alnwick, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Hinds
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: Czeskis
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ruterbories
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Suico
authors.affiliation: Covance Inc., Evansville, IN, 47710, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Royalty
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Demetrio
authors.initials: D
authors.lastname: Ortega
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Pack
authors.affiliation: Clinical Operations, Covance Inc., Leeds, UK.
authors.forename: Syeda L
authors.initials: SL
authors.lastname: Begum
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Annes
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Small
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001682:Biological Availability; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D012449:Safety; D055815:Young Adult
chemical_list: D001569:Benzodiazepines; C568301:evacetrapib
keywords: bioavailability; cholesteryl ester transfer protein; evacetrapib; pharmacokinetics; tracer