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.

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.

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.

An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.

Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.

Single-Dose Pharmacokinetics and Metabolism of the Oral Decongestant Phenylephrine HCl in Children and Adolescents.

INTRODUCTION: Pediatric data for phenylephrine, a decongestant used in cold medicines, are limited. This study characterized the pharmacokinetics and metabolism of phenylephrine HCl in children aged 2-17 years. METHODS: Forty-one children experiencing nasal congestion were dosed orally with phenylephrine HCl from 2.5 to 10 mg using a modified weight-age schedule. Plasma from blood samples collected up to 4.5 h after dosing was analyzed for phenylephrine. Urine collected over 24 h was analyzed for phenylephrine and metabolites. Blood pressure and pulse were measured after each blood sampling, and electrocardiograms were recorded before and after dosing. Pharmacokinetic parameters were estimated using noncompartmental methods. RESULTS: Mean phenylephrine total exposure (AUC∞) for children aged 2-5, 6-11, and 12-17 years was 672, 830, and 1020 pg∙h/mL, and mean maximum concentration (Cmax) was 477, 589, and 673 pg/mL, respectively. Times to peak concentration (Tmax) ranged from 0.17 to 1.5 h, and elimination half-life (t½,ß) was short from 1.2 to 1.6 h. Oral clearance (CL/F) increased with age, but with allometric scaling for body size, this trend reversed as scaled clearance (CL/F,scaled) was modestly higher in youngest children. No clinically relevant changes in vital signs or electrocardiograms were observed. CONCLUSION: A dosing schedule with additional weight-age increments would provide more consistent systemic concentrations as children age and receive the next higher dose. No developmental delays in clearance mechanisms were apparent when oral clearance was scaled for body size. Phenylephrine pharmacokinetics and metabolism were consistent with adult data, although AUC∞ for the youngest group and Cmax for all pediatric groups were lower. Single doses of phenylephrine HCl were well tolerated. TRIAL REGISTRATION: Clintrials.gov NCT00762567, registered 30 September 2008.

Objective and self-reported evidence of dextromethorphan antitussive efficacy in children, aged 6-11 years, with acute cough due to the common cold.

OBJECTIVE: To determine objective and subjective endpoints most suitable for evaluating antitussive efficacy of dextromethorphan hydrobromide (DXM) in children. Spontaneous resolution of acute cough and large placebo effects are impediments to evaluating antitussive efficacy. Another impediment is paucity of age-appropriate, validated cough assessment tools. METHODS: This was a multiple-dose, double-blind, placebo-controlled, randomized, pilot clinical study in children, aged 6-11 years, with cough due to the common cold. Eligible subjects met entry criteria and qualified by completing a run-in period where coughs were recorded with a cough monitor after they were dosed with sweet syrup. They were subsequently randomized to receive DXM or placebo over 4 days. Coughs were recorded during the initial 24 h; subjective assessments of cough severity and frequency were self-reported daily during treatment. RESULTS: Data from 128 evaluable subjects (67 DXM; 61 placebo) were analyzed. Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. Also, greater reductions in cough severity and frequency were self-reported with DXM. These findings were statistically significant and medically relevant. No effects were detected between treatments for nighttime cough rates or impact of cough on sleep. Multiple doses of DXM and placebo were generally well-tolerated. CONCLUSION: Evidence of DXM antitussive efficacy was shown in children using objective and subjective assessment tools validated in pediatric populations. Diurnal variation of cough frequency over 24 h reduced the assay sensitivity needed to detect treatment differences at nighttime, as coughs/hour decreased during sleep for both groups.

A randomized, placebo-controlled, exploratory trial of Ibuprofen and pseudoephedrine in the treatment of primary nocturnal enuresis in children.

This exploratory randomized, double-blind, double-dummy, placebo-controlled trial of 14 days duration conducted in 22 primary care practices in the United States was used to compare the efficacy of ibuprofen and pseudoephedrine, administered alone or in combination, to placebo for the treatment of primary nocturnal enuresis (PNE) in children aged 6 to 11 years. Ibuprofen (IBU) and pseudoephedrine (PSE) are not approved for the treatment of PNE. Three hundred eighteen children with PNE were enrolled. Eligible children had >or= 8 wet nights during a 14-day baseline. Each child was randomly assigned to 1 of 4 treatment groups: IBU 12.5 mg/kg and PSE HCl 15 or 30 mg (depending on weight) (n = 82), IBU 12.5 mg/kg (n = 78), PSE HCl 15 or 30 mg (n = 76), or placebo (n = 82). Treatment was administered orally at bedtime for 14 days. Caregivers recorded whether the child was wet or dry each night in a daily diary. Children in the IBU alone and IBU and PSE combined groups had greater mean reductions from baseline in the number of wet nights (primary end point) compared to children receiving placebo (-2.9, -2.9, and -1.4, respectively, P < .005); PSE alone (-1.8) was not significantly different from placebo. Children in these groups also had greater mean percentage reductions in the number of wet nights compared to placebo-treated children (26%, 28%, and 12%, respectively). Although not always statistically significant, secondary end points improved in the IBU alone and IBU and PSE combined treatment groups, which included decreases in mean number of wet nights and decreases in the number and percentage of children with >or= 50%, 40%, 30%, or 25% reductions in number of wet nights. Children responding to treatment had larger mean bladder capacities and larger mean percentage of predicted bladder capacities than children who did not respond in each treatment group. No significant differences in adverse events were found among treatment groups. In conclusion, in this exploratory study in children aged 6 through 11 years, IBU provided a beneficial effect in the treatment of PNE compared to placebo, whereas PSE did not. The addition of PSE to IBU did not enhance or diminish the efficacy of IBU. All treatments were well tolerated.

A Multicenter, Randomized, Placebo-Controlled Study of Pseudoephedrine for the Temporary Relief of Nasal Congestion in Children With the Common Cold.

This multicenter, double-blind, placebo-controlled, randomized study was designed to evaluate the efficacy and safety of pseudoephedrine hydrochloride 30-mg tablets in children aged 6 to 11 years for the temporary relief of nasal congestion due to the common cold. The primary efficacy end point was the weighted sum of the change from baseline in instantaneous nasal congestion severity score over the period from 1 to 8 hours following the first dose of study drug on day 1. Safety assessments included adverse events, sleepiness ratings, and vital signs. Pseudoephedrine was superior to placebo in reducing instantaneous nasal congestion severity in pediatric children over the first 8 hours after dosing on day 1 (least squares mean difference between treatment groups was 1.2; P = .029). Overall, secondary end points associated with nasal congestion were supportive on day 1, whereas secondary end points on day 2 were only numerically favorable. Somnolence was reported in a greater percentage of children on pseudoephedrine compared to placebo (71.9% vs 63.9%), while similar percentages of children in the same respective groups reported insomnia (34.4% and 38.9%) and nervousness (20.0% and 23.6%).Pseudoephedrine provides temporary relief of nasal congestion associated with the common cold in children 6 to <12 years of age at the current over-the-counter monograph dose. Multiple dosing of pseudoephedrine for up to 7 days, when given as needed for symptom relief, was generally safe in this population of children with the common cold.

Single-Dose Pharmacokinetic Study of Diphenhydramine HCl in Children and Adolescents.

Diphenhydramine pharmacokinetics were characterized following a single oral dose in children aged 2 to 17 years using a weight- and age-based dosing schedule with more tiers than the current age-based dosing schedule recommended by the nonprescription drug monograph. This study was conducted in 42 subjects, aged 2 to 17 years. Doses were based on a weight-age dosing schedule, ranging from 6.25 to 50 mg. An oral dose was administered with water about 2 hours after a light breakfast. Plasma samples were obtained up to 48 hours after dosing and analyzed for diphenhydramine. Pharmacokinetic parameters were estimated using noncompartmental methods, and the relationship of oral clearance with age was assessed using linear regression. Over an 8-fold range of doses, Cmax and AUC increased ∼90 % to ∼140% across age groups, with a similar Tmax (1.5 hours). Oral CL/F increased with age, but after allometric scaling, no maturation-related change in CL/F was apparent. Mild somnolence was the most commonly reported adverse event (95% of the subjects). A weight-age dosing schedule using an 8-fold range of doses achieved Cmax and AUC that increased about 2-fold across age groups. No effect of maturation on CL/F was observed after allometric scaling.

Aminotransferase activities in healthy subjects receiving three-day dosing of 4, 6, or 8 grams per day of acetaminophen.

INTRODUCTION: This multiple-dose pharmacokinetic study has a randomized, double-blind, placebo-controlled, parallel-group design with three dosing regimens. Healthy subjects received repeated doses of acetaminophen (4 then 6 g/d or 4 then 8 g/d) or placebo. METHODS: The disposition of acetaminophen and its metabolites and the tolerability of increased acetaminophen doses over 3 days of continuous consumption were characterized. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities measured throughout the study were consistent across the acetaminophen 4, 6, and 8 g/d dose levels and with placebo. RESULTS: Serum aminotransferase activities did not exceed the upper limit of the reference range (ULRR), except for one subject with an AST of 43 U/L (ULRR, 42 U/L), which was not considered clinically significant. All doses were generally well tolerated. CONCLUSIONS: In a multiple-dose pharmacokinetics study of 4, 6, and 8 g/d of acetaminophen for 3 days, multiple aminotransferase determinations demonstrated no clinically important elevations at 1, 1.5, or 2 times the maximum recommended acetaminophen dose.

Pharmacokinetics, safety, and cardiovascular tolerability of phenylephrine HCl 10, 20, and 30 mg after a single oral administration in healthy volunteers.

BACKGROUND AND OBJECTIVES: Phenylephrine HCl 10 mg has been used as a nasal decongestant for over 50 years, yet only limited pharmacokinetic and metabolic data are available. The purpose of this study was to evaluate single-dose pharmacokinetics and safety of phenylephrine HCl 10, 20, and 30 mg and to assess cardiovascular tolerability compared with baseline and placebo in healthy volunteers. METHODS: Twenty-eight adults were enrolled in this randomized, double-blind, placebo-controlled, single-dose, four-treatment crossover study. Subjects remained housed for 6 days to permit time-matched, serial measurements of pulse, blood pressure, and electrocardiograms (ECGs) for baseline and complete treatments on consecutive days. After fasting overnight, subjects were dosed with oral phenylephrine HCl 10, 20, or 30 mg or placebo. Pharmacokinetic blood samples were collected over 7 h, whereas pulse, blood pressure, and ECGs were measured over 12 h. Urine was collected over each 24-h period to quantify phenylephrine and metabolites. RESULTS: After oral administration, phenylephrine was rapidly absorbed with median times to maximum plasma concentrations (t max) from 0.33 to 0.5 h. For phenylephrine HCl 10, 20, and 30 mg, the mean (standard deviation) maximum concentration (C max) was 1354 (954), 2959 (2122), and 4492 (1978) pg/mL, and total systemic exposure [area under the plasma concentration-time curve from time zero to infinity (AUC∞)] was 955.8 (278.5), 2346 (983.8), and 3900 (1764) pg·h/mL, respectively. Both parameters increased disproportionally with increasing dose, as ß >1 in the power model. Negligible amounts of phenylephrine and phenylephrine glucuronide were excreted in urine. With increasing dose, percentages by dose of phenylephrine sulfate decreased, whereas percentages of 3-hydroxymandelic acid increased. Eight subjects reported nine mild adverse events; one (somnolence) was deemed to be treatment related. Means of time-matched differences in pulse and blood pressure from baseline showed similar fluctuations over 12 h among phenylephrine HCl doses and placebo, although small differences in systolic pressure were observed during the initial 2 h. No apparent dose-related effects were observed for Fridericia-corrected QT interval (QTcF) values, and individual changes from time-matched baseline (DQTcF). CONCLUSIONS: Maximum and total systemic exposures following singe doses of phenylephrine HCl 10, 20, and 30 mg increased disproportionally with increasing dose. Safety and cardiovascular tolerability were comparable among doses and placebo.

Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.