Absolute bioavailability of evacetrapib in healthy subjects determined by simultaneous administration of oral evacetrapib and intravenous [¹³C₈]‐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 [13C8]‐evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [13C8]‐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 13C‐labeled IV microdose tracer at about 1/1000th 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.

Late-Stage 18O Labeling of Primary Sulfonamides via a Degradation-Reconstruction Pathway

“…Synthetic reagents containing the traditionally used isotopes 2 H, 13 C, and 15 N [4b, 6] can also be costly and only provide one mass unit increase for each atom. Moreover, the 2 H isotope is not desirable for bioavailability studies as deuterium is often labile to metabolic pathways, [7] and can also exhibit problematic chromatographic behavior [8] by failing to co-elute with the nonlabeled analyte of interest. [9] Compared to 2 H, 13 C, or 15 N isotopes, developing sulfonamides tracers with a doubly-labeled oxygen-18 ( 18 O) sulfonyl would be a far more efficient strategy for achieving the required mass differential of the SIL compound, due to the overall four-mass unit increase.…”

Late-Stage 18O Labeling of Primary Sulfonamides via a Degradation-Reconstruction Pathway

“…Synthetic reagents containing the traditionally used isotopes 2 H, 13 C, and 15 N [4b, 6] can also be costly and only provide one mass unit increase for each atom. Moreover, the 2 H isotope is not desirable for bioavailability studies as deuterium is often labile to metabolic pathways, [7] and can also exhibit problematic chromatographic behavior [8] by failing to co-elute with the nonlabeled analyte of interest. [9] Compared to 2 H, 13 C, or 15 N isotopes, developing sulfonamides tracers with a doubly-labeled oxygen-18 ( 18 O) sulfonyl would be a far more efficient strategy for achieving the required mass differential of the SIL compound, due to the overall four-mass unit increase.…”

34S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds

“…Due to the significant sensitivity improvements of mass spectrometry instrumentation over the past decade, SIL microdose methods have been evolving for determining absolute bioavailability. In these approaches, a therapeutic dose of drug via the oral route is administered and, at the expected T max , a microdose (100–200 μg) of an SIL‐drug is administrated through the intravenous (IV) route . The requirements for the SIL‐compound as microdose tracer are different from the requirements for the SIL‐IS.…”