药代动力学
耐受性
医学
对乙酰氨基酚
药理学
解热药
最大值
不利影响
止痛药
皮疹
安慰剂
药品
红斑
毒性
内科学
外科
病理
替代医学
作者
Cathy K. Gelotte,Amy M. Vakil,Joris Berwaerts,Brenda Zimmerman,Gary Eichenbaum,Christopher M. Flores,Edwin K. Kuffner
标识
DOI:10.1016/j.yrtph.2022.105236
摘要
JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50–6000 mg) and multiple (250–2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1–3 h, except at high doses at which Cmax was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t½ values that ranged from 8 to 10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses.
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