Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

Wong, Simon; Ma, Shuguang

doi:10.1016/b978-0-12-817134-9.00004-0

Overcoming Obstacles in Drug Discovery and Development 2023

DOI: 10.1016/b978-0-12-817134-9.00004-0

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Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

Simon Wong

Shuguang Ma

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2024

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Cited by 2 publications

References 300 publications

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Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

Li,

Lindmark,

Amilon

et al. 2024

Pharmacology Res & Perspec

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In this study, the mass balance, pharmacokinetics (PK) and metabolism of atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor, were investigated in healthy male subjects. A single oral dose of 200 mg [14C]atuliflapon suspension was administered to six healthy male subjects. Mass balance, PK and metabolite profiles of atuliflapon were analyzed using radioactivity monitoring and liquid chromatography with mass spectrometry analysis. The safety of atuliflapon was assessed during the study. Atuliflapon was rapidly absorbed with a median tmax of 1.5 h, followed by a biphasic decline in plasma exposure rendering a terminal half‐life of ~20 h. Unchanged atuliflapon was the predominant radioactive component in plasma, accounting for 40.1% of the total drug‐related exposure (DRE), while a direct N‐glucuronide was the only metabolite exceeding 10% of DRE, accounting for 20.9%. Renal excretion of intact atuliflapon accounted for <1% of the administered dose. In total 85.2% of administered radioactivity was recovered over 312 h with 79.3% and 5.9% in feces and urine, respectively. Parent atuliflapon contributed to approximately 40% of the recovered dose in excreta, while metabolites resulting from phase 1 oxidative pathways accounted for more than 30% of the excreted dose. Overall, a single oral dose of 200 mg [14C]atuliflapon suspension was well tolerated in healthy male subjects. The human metabolism and disposition data obtained will support future development and submissions of atuliflapon as a potential candidate drug for the treatment of cardiovascular, cardiorenal, and respiratory indications.

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Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

Li,

Lindmark,

Amilon

et al. 2024

Pharmacology Res & Perspec

View full text Add to dashboard Cite

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Mid-infrared trace detection with parts-per-quadrillion quantitation accuracy: Expanding frontiers of radiocarbon sensing

Jiang,

McCartt

2024

Proc. Natl. Acad. Sci. U.S.A.

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Detection sensitivity is a critical characteristic to consider during selection of spectroscopic techniques. However, high sensitivity alone is insufficient for spectroscopic measurements in spectrally congested regions. Two-color cavity ringdown spectroscopy (2C-CRDS), based on intra-cavity pump–probe detection, simultaneously achieves high detection sensitivity and selectivity. This combination enables mid-infrared detection of radiocarbon dioxide ( 14 CO 2 ) molecules in room-temperature CO 2 samples, with 1.4 parts-per-quadrillion (ppq, 10 − 15 ) sensitivity (average measurement precision) and 4.6-ppq quantitation accuracy (average calibrated measurement error for 21 samples from four separate trials) demonstrated on samples with 14 C/C up to ∼ 1.5 × natural abundance ( ∼ 1,800 ppq). These highly reproducible measurements, which are the most sensitive and quantitatively accurate in the mid-infrared, are accomplished despite the presence of orders-of-magnitude stronger, one-photon signals from other CO 2 isotopologues. This is a major achievement in laser spectroscopy. A room-temperature-operated, compact, and low-cost 2C-CRDS sensor for 14 CO 2 benefits a wide range of scientific fields that utilize 14 C for dating and isotope tracing, most notably atmospheric 14 CO 2 monitoring to track CO 2 emissions from fossil fuels. The 2C-CRDS technique significantly enhances the general utility of high-resolution mid-infrared detection for analytical measurements and fundamental chemical dynamics studies.

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Design, conduct, and interpretation of human mass balance studies and strategies for assessing metabolites-in-safety testing (MIST) in drug development

Cited by 2 publications

References 300 publications

Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

Disposition of orally administered atuliflapon, a novel 5‐lipoxygenase‐activating protein inhibitor in healthy participants

Mid-infrared trace detection with parts-per-quadrillion quantitation accuracy: Expanding frontiers of radiocarbon sensing

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