Metabolism and disposition of JNJ-10450232 (NTM-006) in rats, dogs, monkeys and humans

Heng-Keang Lim; Jie Chen; Wing Lam; Yong Gong; Laurent Leclercq; Jose Silva; Rhys Salter; Joris Berwaerts; Cathy K Gelotte; Amy M Vakil; Gary E Eichenbaum; Edwin K Kuffner; Christopher M Flores

doi:10.1016/j.yrtph.2023.105379

Metabolism and disposition of JNJ-10450232 (NTM-006) in rats, dogs, monkeys and humans

Regul Toxicol Pharmacol. 2023 Mar 16:105379. doi: 10.1016/j.yrtph.2023.105379. Online ahead of print.

Authors

Affiliations

¹ Drug Metabolism and Pharmacokinetics, Janssen Research and Development, Spring House, PA, USA.
² Drug Metabolism and Pharmacokinetics, Janssen Research and Development, Beerse, Belgium.
³ Amgen Inc, Thousand Oaks, CA, USA.
⁴ Johnson & Johnson Consumer Inc, Fort Washington, PA, USA.
⁵ Johnson & Johnson, New Brunswick, NJ, USA.
⁶ Johnson & Johnson Consumer Inc, Fort Washington, PA, USA. Electronic address: EKuffner@its.jnj.com.
⁷ Janssen Research & Development, San Diego, CA, USA.

PMID: 36931586
DOI: 10.1016/j.yrtph.2023.105379

Abstract

JNJ-10450232 (NTM-006), a novel non-opioid, non-nonsteroidal anti-inflammatory drug with structural similarities to acetaminophen, demonstrated anti-pyretic and/or analgesic activities in preclinical models and humans and reduced potential to cause hepatotoxicity in preclinical species. Metabolism and disposition of JNJ-10450232 (NTM-006) following oral administration to rats, dogs, monkeys and humans are reported. Urinary excretion was the major route of elimination based on recovery of 88.6% (rats) and 73.7% (dogs) of oral dose. The compound was extensively metabolized based on low recovery of unchanged drug in excreta from rats (11.3%) and dogs (18.4%). Clearance is driven by O-glucuronidation, amide hydrolysis, O-sulfation and methyl oxidation pathways. The combination of metabolic pathways driving clearance in human is covered in at least one preclinical species despite a few species-dependent pathways. O-Glucuronidation was the major primary metabolic pathway of JNJ-10450232 (NTM-006) in dogs, monkeys and humans, although amide hydrolysis was another major primary metabolic pathway in rats and dogs. A minor bioactivation pathway to quinone-imine is observed only in monkeys and humans. Unchanged drug was the major circulatory component in all species investigated. Except for metabolic pathways unique to the 5-methyl-1H-pyrazole-3-carboxamide moiety, metabolism and disposition of JNJ-10450232 (NTM-006) are similar to acetaminophen across species.

Keywords: Acetaminophen; Disposition; Drug metabolism; Non-opioid; Nonclinical; Novel analgesic.