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.

Introduction:Prescription and most over-the-counter medicines are required to have child-resistant packaging and/or labeled with instructions "Keep out of reach of children." Although medication organizers are not required to have such design features or instructions, these could help prevent unsupervised ingestions by children. Commonly purchased medication organizers were evaluated for child-resistant design features and instructions for safe use to prevent unsupervised ingestions.Methods:The 29 best-selling medication organizers on Amazon.com were identified, and product identifiers, design characteristics, and safety characteristics were recorded using a standardized instrument.Results:Of the 29 medication organizers, none claimed to be child resistant. Only 31% provided a specific warning that the organizer was not child resistant on the packaging; only 41% communicated "Keep out of reach of children." Most organizers (59%) provided neither a warning that the organizer was not child resistant nor instructions to store out of reach of children. The majority of organizers (79%) shared the following characteristics: plastic construction, rectangular shape, nonelectronic flip-top opening mechanisms, and 7-day usage.Conclusions:Opportunities exist for manufacturers of medication organizers to improve child-resistant product design, provide information to help prevent unsupervised ingestions (directions to keep the device out of the reach of children), and help to reduce unsupervised ingestions.

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 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.

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.

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.

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (<= 4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death - thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g. baseline glutathione (GSH) levels, pharmacokinetics, and capacity of hepatic antioxidants) leads to potential differences in carcinogenic hazard potential at different dosing schemes: maximum labeled doses of 4 g/day, repeated doses above the maximum labeled dose (>4-12 g/day), and acute overdoses of acetaminophen (>15 g). This was achieved by performing simulations of acetaminophen exposure in thousands of diverse virtual patients scenarios using the DILIsym (R) Quantitative Systems Toxicology (QST) model. Simulations included assessments of the dose and exposure response for toxicity and mode of cell death based on evaluations of the kinetics of changes of: GSH, N-acetyl-pbenzoquinone-imine (NAPQI), protein adducts, mitochondrial dysfunction, and hepatic cell death. Results support that, at therapeutic doses, cellular GSH binds to NAPQI providing sufficient buffering capacity to limit protein adduct formation and subsequent oxidative stress. Simulations evaluating repeated high-level supra therapeutic exposures or acute overdoses indicate that cell death precedes DNA damage that could result in carcinogenicity and thus acetaminophen does not present a carcinogenicity hazard to humans at any dose.

OBJECTIVE:Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies.METHODS:Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study.RESULTS:A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses.CONCLUSIONS:Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Published analyses have noted elevated alanine aminotransferase (ALT) activity in patients taking up to 4000 mg/day of acetaminophen. Data from 3 osteoarthritis trials of acetaminophen 3900–4000 mg/day in which ALT and aspartate aminotransferase (AST) were recorded within approximately 2 weeks of therapy initiation were retrospectively analyzed. Patients with baseline ALT or AST above the upper limit of the reference range (ULRR) were excluded. Among 466 patients, 376 (80.7%) had no ALT elevations within approximately 2 weeks of treatment initiation. Elevations >1.5 and >3.0 times ULRR occurred in 4.5% and 0.9% of patients, respectively. Elevations were transient as most resolved (72.9%) or declined (22.4%) with continued treatment beyond 2 weeks. Within approximately 2 weeks of therapy initiation, no patient had ALT > 5 times ULRR or ALT > 3 times ULRR combined with bilirubin >2 times ULRR. ALT elevations were transient and asymptomatic; almost all resolved or declined while on continued therapy and appear not to be clinically important. Clinical trials.gov ID numbers: NCT00240799, NCT00240786

Background: A standardized approach to dosing acetaminophen in pediatric populations was published in 1983. That review proposed specific weight-related dosing for infants and children weighing 6 through 95 lb and an age-based schedule for children aged <4 months through 11 years. Subsequent clinical studies evaluating these and alternative doses of acetaminophen supported the recommended 10-15-mg/kg dose.Objective: This article reviewed published and unpublished pediatric antipyretic data to provide a critical assessment of the 10-15-mg/kg oral dose and the current pediatric oral dosing schedules for acetaminophen.Methods: Published literature and unpublished clinical trials that evaluated the antipyretic efficacy of acetaminophen in children were reviewed. The PubMed database was searched using the term acetaminophen or paracetamol, with study criteria limited to randomized, controlled trials; oral dosing; patient age <12 years; and publication between 1982 and August 2012. All of the sponsor's unpublished antipyretic clinical studies completed between 1980 and August 2012 and involving at least 1 oral-formulation acetaminophen-only treatment arm were identified. Data from published literature containing sufficient detail to verify doses; dosing frequency; and, when necessary, estimates from figures, and from acetaminophen arms of the unpublished studies were analyzed.Results: Thirteen unpublished trials enrolled 705 children to receive an oral dose of 10-15 mg/kg of acetaminophen. This dose resulted in a rapid onset of temperature reduction, with a maximum temperature decrement of 3 hours following administration. Results from 40 published clinical trials in which 2332 children received oral acetaminophen for fever support these findings. The most common adverse events reported in any of the reported studies were gastrointestinal in nature and generally mild in intensity.Conclusions: Data support the recommended 10-15-mg/kg oral dose and demonstrate that the age and weight schedules for over-the-counter acetaminophen proposed in 1983 remain appropriate. (C) 2013 Published by Elsevier HS Journals, Inc.

To the Editor: We have had recent cause to review this article and have noted some discrepancies in the way that some of the diphenhydramine blood levels were reported. In Table 2, the blood level of diphenhydramine is listed as 0.87 mg/100 mL and 0.69 mg/100 mL for case 13 and case 14 respectively. In Table 3, the lowest value in the range of blood diphenhydramine levels is listed as 0.087 mg/L and 0.069 mg/L for adults and children respectively. In Table 6, the lowest value in the range of blood diphenhydramine levels is listed as 0.87 mg/L and 0.69 mg/L for adults and children respectively. In the article by Shkrum et al, the primary reference for cases 13 and 14, blood diphenhydramine levels of 0.87 mg/100 mL and 0.69 mg/100 mL are reported for a 25year-old male and a 17-year-old female respectively. The level reported in Table 6 and Table 3 appear to be inaccurate by a factors of 10 and 100 respectively, compared with the levels reported in the primary reference. This highlights common mistakes that can be made when communicating, reporting or abstracting levels of any drug.

We appreciate Dr. Fujita’s valuable input regarding an animal model of chronic endotoxemia and the role of regulatory T cells (Tregs) in liver disease. Cani and colleagues recently reported that a high-fat diet increases plasma lipopolysaccharide (LPS) level.1 Chronic infusion of LPS in mice fed a normal diet causes a metabolic response similar to high-fat feeding, including obesity, insulin resistance, and increased liver triglyceride content. In this sense, the high-fat diet mouse model that we use represents a model of chronic endotoxemia. Our acute exogenous LPS experiments merely reflect an exacerbated inflammatory status that helped us to determine the role of Tregs in modulation of hepatic inflammation under a fatty liver condition.2 Tregs express several members of Toll-like receptors (TLR). Exposing Tregs to LPS induces up-regulation of several activation markers and enhances Treg survival and proliferation.3 In addition, LPS treatment increases Treg suppression efficiency in vitro and in vivo. Therefore, it will be interesting to compare the number and the function of hepatic Tregs in the model of chronic exogenous LPS infusion to the model of high-fat diet–induced fatty liver disease.

Background: In two recent osteoarthritis trials, alanine aminotransferase (ALT) elevations were observed more frequently in patients receiving acetaminophen 3.9 g daily than in patients receiving placebo, and the rates were higher than aminotransferase values observed in some previous osteoarthritis studies with acetaminophen.Objective: To retrospectively analyze ALT data from McNeil osteoarthritis clinical studies involving acetaminophen in order to assess the frequency and magnitude of ALT elevations and rate of ALT resolution while patients remained on acetaminophen treatment. A review of the literature revealed a few reports of isolated aminotransferase elevations occurring during acetaminophen therapy, but these reports were not included in the analysis because they did not include enough information to evaluate the frequency, magnitude, and rate of ALT while patients remained on acetaminophen treatment.Research design and methods: Nine controlled clinical trials were identified in which at least one of the treatments was acetaminophen alone. Studies were included if patients had ALT and aspartate aminotransferase (AST) values obtained at baseline and an ALT value at an additional visit after initiating therapy. Seven studies met these criteria and were included in this analysis. In these studies, patients received acetaminophen 1950-4000 mg/ day for 4 weeks up to 12 months. Laboratory testing was performed at weeks 0 and 4 in the three 4-week studies; at weeks 0, 2, 4, 8, and 12 in the two 12-week studies; at weeks 0, 1, 2, 4, 6, 8, and 13 in the 13-week study; and at months 0, 1, 3, 6, 9, and 12 in the 12-month study. The pooled data set consisted of patient demographics, dosing records, aminotransferase and bilirubin laboratory values, and adverse events.Results: There were no reports of hepatotoxicity or hepatic failure in any acetaminophen-acetaminophen-treated patient (treated n = 1530). In the seven studies,1039 patients had both baseline AST and ALT activity <= upper limit of the reference range and an on-treatment ALT measurement. While on long-term acetaminophen treatment, 181 of 1039 (17.4%) patients had an ALT value that exceeded the upper limit of the reference range. None of the 1039 patients had an on-treatment ALT level > 3 times upper limit of the reference range in conjunction with a serum bilirubin > upper limit of the reference range, and no patient had an ALT level > 10 times upper limit of the reference range. Of the 1039 patients, 44 (4.2%) had an on-treatment ALT level > 1.5 times upper limit of the reference range, and 31 of the 44 patients had a subsequent measurement of ALT. Of these 31 patients, 29 (93.5%) had documented resolution or decreasing ALT while on treatment. An ALT level > 1.5 times upper limit of the reference range was not associated with a higher frequency of symptoms potentially related to hepatic origin. Limitations: The studies included in this analysis were limited to McNeil studies, none of which were designed to specifically evaluate the patterns of ALT activity. Thus, the incidence of ALT elevations after any specific duration of dosing, and the temporal pattern of ALT elevations, cannot be accurately determined. In addition, methodological differences existed across the studies.Conclusion: This analysis involving > 1000 acetaminophen-treated patients shows that low-level, transient ALT elevations usually resolve level, or decrease with continued acetaminophen treatment, are unaccompanied by signs or symptoms of liver injury, and, as such, appear to be clinically insignificant. Maximum recommended daily doses of acetaminophen did not cause liver failure or dysfunction.

Acetaminophen poisoning is the most common cause of medication overdose death in the United States. While most patients can be safely managed outside the ICU, serious toxicity can result in hepatic failure and death. N-acetylcysteine has been shown to prevent liver injury when administered early and reduce mortality for patients with hepatic failure. The proposed mechanism of acetaminophen toxicity and N-acetylcysteine therapy are discussed, as well as extrahepatic toxicity of acetaminophen. Other topics that are discussed include the interaction of ethanol consumption and acetaminophen toxicity and recent advances in the management of acetaminophen poisoning.