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

Abstract

AUC, area under the plasma concentration-time curve AUC inf , area under the plasma concentration-time curve from dosing extrapolated to infinity AUC last , area under the plasma concentration-time curve from dosing to last measurable concentration AUC 0-96h , area under the plasma concentration-time curve from 0-96 hours CL/F, apparent total body clearance of drug from plasma CL R , renal clearance of drug from plasma C max , maximum observed plasma concentration CV, coefficient of variation DRM, drug-related material hADME, human absorption, distribution, metabolism, and excretion HF, heart failure HFpEF, heart failure with preserved ejection fraction This article has not been copyedited and formatted. The final version may differ from this version.

Biotransformation of the Novel Myeloperoxidase Inhibitor AZD4831 in Preclinical Species and Humans

“…This article describes the biotransformation of AZD4831 in preclinical species, healthy volunteers, and HFpEF patients and complement the human mass balance and PK studies which are reported separately (Bhattacharya et al, 2022). In total, 20 metabolites were identified in mice, rats, dogs, and humans.…”

“…Department of Health and Human Services, 2020). In the 14 C studies, the same metabolites were observed in rat plasma, although in human plasma, two additional minor metabolites were detected, M16 and M17, representing the desulfurized or hydroxylated carbamoyl glucuronides, respectively (Bhattacharya et al, 2022). As far as safety of those metabolites concerns, M16 and M17 were observed at levels less than 6% of DRE in human plasma and both represent stable carbamoyl glucuronides that would generally be regarded to be of no safety concern.…”

“…For the rat ADME study, fractional collection and off-line radioactivity detection was used to generate metabolite profiles, while LSC analysis was used to measure total radioactivity. Details of the human ADME study are presented separately ( Bhattacharya et al, 2022 ).…”

“…In addition, we report the assessment of in vitro protein binding of AZD4831 and its major metabolite across preclinical species and humans to better understand its impact on the metabolism of AZD4831. Results of the human absorption, distribution, metabolism and excretion (ADME) study are reported and discussed in detail separately ( Bhattacharya et al, 2022 ).…”

The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses

“…This scenario considers the impact of renal impairment on mitiperstat exposure. Renal elimination is the major route of mitiperstat excretion, with 32%–44% of the dose excreted unchanged in urine 20 . In patients with moderate to severe renal impairment, exposure is expected to increase by up to two‐fold compared with healthy volunteers, therefore 5 mg dose in patients is expected to have exposure similar to that after 10 mg in healthy volunteers.…”