JNJ-10450232 (NTM-006), A novel non-opioid with structural similarities to acetaminophen, produces relatively long-lasting analgesia after a single dose in patients undergoing 3rd molar extraction.

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.

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

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.

Preclinical safety assessment of JNJ-10450232 (NTM-006), a structural analog of acetaminophen, that does not cause hepatotoxicity at supratherapeutic doses.

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.

First-in-human study to evaluate the safety, tolerability and pharmacokinetics of a novel analgesic and antipyretic drug with structural similarity to acetaminophen.

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.

Assessment of the biochemical pathways for acetaminophen toxicity: Implications for its carcinogenic hazard potential.

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.

Application of the DILIsym® Quantitative Systems Toxicology drug-induced liver injury model to evaluate the carcinogenic hazard potential of acetaminophen.

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® 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-p-benzoquinone-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 supratherapeutic 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.

A critical review of the acetaminophen preclinical carcinogenicity and tumor promotion data and their implications for its carcinogenic hazard potential.

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.

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

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.

New insights into root causes of pediatric accidental unsupervised ingestions of over-the-counter medications.

CONTEXT: Changes to regulations, packaging, and labeling and ongoing educational efforts are intended to support appropriate use of medicines. Yet annually poison centers receive > 500 000 reports of accidental or unsupervised exposure to medicines for children under 6 years of age. OBJECTIVE: To identify root (i.e., fundamental and preventable) causes of accidental unsupervised ingestions (AUIs), we designed a questionnaire and conducted a follow-up survey of caregivers who contacted McNeil Consumer Healthcare (McNeil) following an AUI by a child under 12 years of age. METHODS: Reports received between 1 October 2008 and 22 January 2009 were screened retrospectively for specific Medical Dictionary of Regulatory Activities (MedDRA) Preferred Terms relating to AUIs. Using the questionnaire, we collected information about the child, caregiver, medicines involved in AUI, management of AUI, and storage location of medicines. RESULTS: Two hundred twenty reports met inclusion criteria and attempts to contact these caregivers were made throughout a 2-week period in March 2009; caregivers completed the questionnaire for 45 reports. All AUIs occurred in children under 7 years and 56% were boys. In 56% of AUI cases, the child involved was the intended recipient of the medicine; in 71%, a pediatric medicine was involved. Most AUIs occurred in the child's home; most caregivers reported not observing the AUI. Sixty percent of caregivers reported that the medicine involved in AUI was not in the normal storage location when AUI occurred. Among children involved in AUIs, 84% did not experience any symptoms. Seven children experienced mild, self-limiting symptoms which resolved. AUIs often occurred < 24 h after last therapeutic use when the medicine was removed from its normal storage location. CONCLUSIONS: These new insights may help guide-targeted interventions and educational efforts to focus caregivers' attention to reengaging childproofing mechanisms and returning medicines to a secure location, high and out of sight, immediately after use.

Dosing and antipyretic efficacy of oral acetaminophen in children.

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.

Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials.

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 elevations 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-treated patient (n = 1530). In the seven studies, 1039 patients had both baseline AST and ALT activity < or = 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 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.