Application of Accelerator Mass Spectrometry to Characterize the Mass Balance Recovery and Disposition of AZD4831, a Novel Myeloperoxidase Inhibitor, following Administration of an Oral Radiolabeled Microtracer Dose in Humans.

Autor:	Bhattacharya C; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Sandinge AS; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Bragg RA; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Heijer M; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Yan J; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Andersson LC; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Jurva U; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Pelay-Gimeno M; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Vaes WHJ; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., de Ligt RAF; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Gränfors M; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Amilon C; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Lindstedt EL; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Menakuru SR; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Garkaviy P; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Weidolf L; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.)., Gopaul VS; Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland (C.B.); DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (A.-S.S., J.Y., U.J., L.C.A., V.S.G.); Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences (M.H.); and Early Product Development, Pharmaceutical Sciences (M.G.), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom (R.A.B.); TNO, Leiden, The Netherlands (M.P.-G., W.H.J.V., R.A.F.d.L.); Quotient Sciences, Nottingham, United Kingdom (S.R.M.); Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (P.G.); and Formerly BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden (L.W., C.A., E.-L.L.) sashi.gopaul@astrazeneca.com.
Jazyk:	angličtina
Zdroj:	Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2023 Apr; Vol. 51 (4), pp. 451-463. Date of Electronic Publication: 2023 Jan 13.
DOI:	10.1124/dmd.122.001100
Abstrakt:	This study evaluated the mass balance and disposition of AZD4831, a novel myeloperoxidase inhibitor, in six healthy participants using a 14 C-labeled microtracer coupled with analysis by accelerator mass spectrometry (AMS). A single oral dose of 10 mg 14 C-AZD4831 (14.8 kBq) was administered as a solution, and 14 C levels were quantified by AMS in blood, urine, and feces over 336 hours postdose. AZD4831 was rapidly absorbed, and AZD4831 plasma concentrations declined in a biphasic manner, with a long half-life of 52 hours. AZD4831 was eliminated via metabolism and renal excretion. An N-carbamoyl glucuronide metabolite of AZD4831 (M7), formed primarily via UGT1A1, was the predominant circulating metabolite. Presumably, M7 contributed to the long half-life of AZD4831 via biliary elimination and hydrolysis/enterohepatic recirculation of AZD4831. On average, ∼84% of administered 14 C-AZD4831 was recovered by 336 hours postdose (urine, 51.2%; feces, 32.4%). Between 32%-44% of the dose was excreted as unchanged AZD4831 in urine, indicating renal elimination as the major excretory route. Only 9.7% of overall fecal recovery was recorded in the first 48 hours, with the remainder excreted over 48%-336 hours, suggesting that most fecal recovery was due to biliary elimination. Furthermore, only 6% of unchanged AZD4831 was recovered in feces. Overall, the fraction of the administered AZD4831 dose absorbed was high. 14 C-AZD4831 was well tolerated. These findings contribute to increasing evidence that human absorption, distribution, metabolism, and excretion studies can be performed with acceptable mass balance recovery at therapeutically relevant doses and low radiolabel-specific activity using an AMS- 14 C microtracer approach. SIGNIFICANCE STATEMENT: In this study, the human absorption, distribution, metabolism, and excretion (hADME) of the novel myeloperoxidase inhibitor AZD4831 was assessed following oral administration. This included investigation of the disposition of M7, the N-carbamoyl glucuronide metabolite. Resolution of challenges highlighted in this study contributes to increasing evidence that hADME objectives can be achieved in a single study for compounds with therapeutically relevant doses and low radiolabel-specific activity by using an AMS- 14 C microtracer approach, thus reducing the need for preclinical radiolabeled studies. (Copyright © 2023 by The Author(s).)
Databáze:	MEDLINE
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