Safety and Pharmacokinetic (PK) Study of Intravenous (IV) Acetaminophen Administration in Pediatric Inpatients

Study Overview
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Brief Summary
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We are doing this study to find out what happens to acetaminophen in the body after it is given to children through the vein. Children's bodies may handle drugs differently than adults. Understanding how long the drug stays in the body and how the drug is changed or metabolized by the body (called pharmacokinetics) is an important step in learning what the best dose of acetaminophen for children should be. We are also interested in learning about the safety of this medication when given to children.

Detailed Description
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A Prospective, Multi-Center, Randomized, Open-Label, Single and Repeated Dose, 48 Hour Study, of Intravenous Acetaminophen in Pediatric Inpatients to Determine Pharmacokinetics (PK) and Safety in Acute Pain and Fever

Official Title
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A Prospective, Multi-Center, Randomized, Open-Label, Single and Repeated Dose, 48 Hour Study, of Intravenous Acetaminophen in Pediatric Inpatients to Determine Pharmacokinetics (PK) and Safety in Acute Pain and Fever

Conditions
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Pain, Fever

Intervention / Treatment
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* Drug: IV Acetaminophen
* Drug: IV Acetaminophen


Participation Criteria
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Eligibility Criteria
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To be eligible for entry into the Study, Subjects must meet or Subjects' Parent or Guardian must meet, agree with or confirm all of the following criteria: Provide written Informed Consent/Assent prior to participation in the Study Age strata: Full-term Neonates (≤ 28 days old and minimum post conception age of 37 weeks at birth) Infants [29 days to <2 years (yrs) old] 29 days to <6 months 6 to <12 months 12 to <24 months) Children (2 yrs to <12 yrs old) Adolescents (12 yrs to ≤16 yrs old) Inpatient status: are currently inpatients or have an admission scheduled and will soon become an inpatient (e.g., elective surgery) Diagnosis: requires or will require analgesic treatment for acute pain or antipyretic treatment for fever IV access: have a need for IV access for the duration of the Study either due to a nothing by mouth (NPO) status or due to the Investigator's assessment that oral treatment is not optimal (for example, severe nausea or vomiting) The Subject's Parent/Guardian must have the ability to read and understand the Study procedures and have the ability to communicate meaningfully with the Study Investigator and staff Be free of other physical, mental, or medical conditions which, in the opinion of the Investigator after completing the screening assessment, make Study participation inadvisable If a female of child bearing potential, have a negative pregnancy test Exclusion Criteria (Screening) A Subject is NOT eligible for entry if ANY of the following criteria are met: Is not able to comply with the plasma sampling requirements of the Study Has known or suspected hypersensitivity to acetaminophen or the inactive excipients of IV Acetaminophen. Has been taking any acetaminophen-containing product in the 12 hours prior or any of the following in the 48 hours prior to randomization in the Study: probenecid, disulfiram, isoniazide, St. John's wort, skullcap, chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, and valerian Has any significant medical condition that in the opinion of the Investigator contraindicates participation in the Study Has impaired liver function, with evidence of clinically significant liver disease, or other condition that may suggest the potential for an increased susceptibility to hepatic toxicity with IV APAP exposure. For this criterion, a total bilirubin greater than 1.5 times upper limit of normal (ULN) for age or an Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) or Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT) greater than 2.5 times ULN for age will be deemed as evidence of clinically significant (Common Terminology Criteria for Adverse Events [CTCAE] Grade 2) liver dysfunction or disease. Has significantly impaired renal function or known significant renal disease, as evidenced by an estimated glomerular filtration rate (using the Schwartz formula) calculated to be less than 1/3rd of normal for the applicable age strata Has participated in another interventional clinical Study (investigational or marketed product) within 30 days of the planned Study randomization date

Ages Eligible for Study
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Minimum Age: 29 Days
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous (IV) Acetaminophen 15 milligrams/kilogram (mg/kg)<br>Intravenous Acetaminophen administered 15 milligrams/kilogram (mg/kg) every 8 hours (q8h) or every 6 hours (q6h) based age of subject | Drug: IV Acetaminophen<br>* This study will investigate two doses (12.5 milligrams/kilogram (mg/kg) and 15 milligrams/kilogram) based on weight administered every four hours (q4h), every six hours (q6h), or every eight hours (q8h) (depending on age) Neonates: 12.5 mg/kg q6h IV acetaminophen Neonates: 15 mg/kg q8h IV acetaminophen Infants: 12.5 mg/kg q4h IV acetaminophen Infants: 15 mg/kg q6h IV acetaminophen Children: 12.5 mg/kg q4h IV acetaminophen Children: 15 mg/kg q6h IV acetaminophen Adolescents: 12.5 mg/kg q4h IV acetaminophen Adolescents: 15 mg/kg q6h IV acetaminophen<br>* Other names: IV APAP;|
| Experimental: Intravenous (IV) Acetaminophen 12.5 (mg/kg)<br>Intravenous Acetaminophen administered 12.5 milligrams/kilogram (mg/kg) every 6 hours (q6h) or every 4 hours (q4h) | Drug: IV Acetaminophen<br>* This study will investigate two doses (12.5 milligrams/kilogram (mg/kg) and 15 milligrams/kilogram) based on weight administered every four hours (q4h), every six hours (q6h), or every eight hours (q8h) (depending on age) Neonates: 12.5 mg/kg q6h IV acetaminophen Neonates: 15 mg/kg q8h IV acetaminophen Infants: 12.5 mg/kg q4h IV acetaminophen Infants: 15 mg/kg q6h IV acetaminophen Children: 12.5 mg/kg q4h IV acetaminophen Children: 15 mg/kg q6h IV acetaminophen Adolescents: 12.5 mg/kg q4h IV acetaminophen Adolescents: 15 mg/kg q6h IV acetaminophen<br>* Other names: IV APAP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single-dose Maximum Plasma Concentration (Cmax) , Micrograms Per Milliliter (µg/mL) Pharmacokinetics of IV Acetaminophen | Cmax: Maximum Plasma Concentration | Time Zero (just prior to first dose) to 24 hours post first dose | 
| Single-dose Time to Reach Maximum Plasma Concentration [Tmax(h)] Pharmacokinetics of IV Acetaminophen | Tmax: Time to reach maximum plasma concentration (Cmax) | Time Zero (just prior to first dose) to 24 hours post first dose | 
| Multiple-dose Area Und the Curve (AUC) From Time 0 (Predose) to the Time of the Dosing Interval at Steady-state (0-t (µg*h/ml) Pharmacokinetics of IV Acetaminophen | AUC 0-t (µg*h/ml): Area under the plasma concentration versus time curve from time 0 (predose) to the time of the dosing interval at steady-state. | Time Zero (just prior to first dose) to 48 hours post first dose | 
| Multiple-dose Terminal Elimination Half-life [t1/2(h)] Pharmacokinetics of IV Acetaminophen | t1/2: Terminal elimination half-life | 48hrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Reporting at Least One Treatment-Emergent Adverse Event (TEAE) | A TEAE is defined as an adverse event that starts on or after the start of study medication | First dose of study medication to 30 days after the last dose of study medication | 
| Subjects Who Experience at Least One Serious Treatment-Emergent Adverse Event (TEAE) | A Serious Treatment Emergent Adverse Event is defined as any untoward medical occurrence at any dose of IV acetaminophen that; Results in Death, Is life-threatening, Requires inpatient hospitalization or causes prolongation of existing hospitalization, Results in persistent or significant disability/incapacity, Is a congenital anomaly/birth defect, Is an important medical event | First dose to 30 days following last dose of study medication |