Regulatory Toxicology and Pharmacology最新文献

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.

JNJ-10450232 (NTM-006) is a non-opioid, non-NSAID analgesic and antipyretic compound with structural similarity to acetaminophen. Preclinical models show comparable analgesia relative to acetaminophen and no evidence of hepatotoxicity associated with overdose. Moreover, it was safe and generally well tolerated in a First-in-Human Study. This single-dose, single-center, inpatient, randomized, double-blind study in moderate-to-severe acute pain following third molar extraction compared efficacy and safety of 250 mg and 1000 mg JNJ-10450232 (NTM-006), 1000 mg acetaminophen, and placebo during the 24 h following administration. While onset of action of 1000 mg JNJ-10450232 (NTM-006) was relatively slower compared with acetaminophen, its duration of action was sustained up to 24 h being superior beginning 7 h after administration. No clinically important differences among treatment groups in nature or severity of adverse events were observed and no serious adverse events were reported. Increased bilirubin, potentially due to UGT1A1 inhibition and ingestion of blood from oral surgery, was the most commonly reported adverse event and the only event reported by ≥ 5% of subjects across treatment groups. These data support further evaluation of JNJ-10450232 (NTM-006) for the treatment of moderate-to-severe pain. CLINICALTRIALS.GOV ID: NCT02209181.

A mainstay of the analgesic pharmacopeia for nearly seven decades and alone in its class, acetaminophen relieves mild-to-moderate pain and fever, without similar adverse gastrointestinal and cardiovascular effects associated with non-steroidal anti-inflammatory drugs. While safe and effective when used as directed, acetaminophen overdose may produce liver injury. This report describes discovery and pharmacological characterization of JNJ-10450232/NTM-006, an acetaminophen structural analog designed to retain the efficacy and overall safety profile of acetaminophen without risk of hepatotoxicity following overdose. In the carrageenan and complete Freund's adjuvant models of inflammatory pain and yeast model of fever in rats, JNJ-10450232/NTM-006 exhibited statistically significant effects comparable to acetaminophen in both maximal efficacy and potency. In rat pharmacokinetic studies, JNJ-10450232/NTM-006 exhibited a comparable maximal plasma concentration but higher volume of distribution and longer half-life than acetaminophen, potentially conferring an extended duration of action. In a mouse model of liver injury, acetaminophen produced elevations in aspartate and alanine transaminase activities and signs of hepatic necrosis, whereas JNJ-10450232/NTM-006 did not. Finally, following systemic administration, JNJ-10450232/NTM-006 and acetaminophen produced comparable peripheral levels of para-aminophenol and brain levels of pharmacologically active metabolite N-arachidonoyl-phenolamine (AM404), consistent with the hypothesis that both parent molecules are prodrugs and share the same central mechanism of analgesic action. Taken together, these results suggest JNJ-10450232/NTM-006 as a potentially clinically useful analgesic/antipyretic with improved benefit-to-risk ratio compared with current standards of care.

JNJ-10450232 (NTM-006) is a new molecular entity that is structurally related to acetaminophen. A comprehensive non-clinical safety program was conducted to support first-in-human and clinical efficacy studies based on preclinical data suggesting that the compound has comparable or enhanced antinociceptive and antipyretic efficacy without causing hepatotoxicity at supratherapeutic doses. No hepatic toxicity was noted in a mouse model sensitive to acetaminophen hepatotoxicity or in rats, dogs, and non-human primates in 28-day repeat dose toxicity studies at and above doses/exposures at which acetaminophen is known to cause hepatotoxicity. In the 28-day toxicity studies, all treatment-related findings were monitorable and reversible. Methemoglobinemia, which was observed in dogs and to a lesser extent in rats, is also observed with acetaminophen. This finding is considered not relevant to humans due to species differences in metabolism. Thyroid hypertrophy and hyperplasia were also observed in dogs and were shown to be a consequence of a species-specific UGT induction also demonstrated with increased thyroid hormone metabolism. Indirect bilirubin elevation was observed in rats as a result of UGT1A1 Inhibition. JNJ-10450232 (NTM-006) had no toxicologically relevant findings in safety pharmacology or genotoxicity studies. Together, these data supported progressing into safety and efficacy studies in humans.