Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants

Abstract

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.

Trial registration: ClinicalTrials.gov NCT01635101.

Keywords: acetaminophen; acute postoperative pain; infants; neonates; opioids.

Conflict of interest statement

Gregory B. Hammer, MD, has no conflicts of interest. Lynne G. Maxwell, MD, received research funding for an intravenous acetaminophen clinical trial (3/2013‐9/2016) from Cadence Pharmaceuticals (acquired by Mallinckrodt). Brad M. Taicher, DO, MBA, has no conflicts of interest. Mihaela Visoiu, MD, is a consultant for Pacira. David S. Cooper, MD, MPH, is on the Mallinckrodt Speakers Bureau. Peter Szmuk, MD, has no conflicts of interest. Jia Lu, PhD, is a former employee of Mallinckrodt. Krishna Devarakonda, PhD, FCP, is a former employee of Mallinckrodt. Leng Hong Pheng, PhD, and Nathalie H. Gosselin, PhD, are associated with Certara.

© 2019 Mallinckrodt. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Population PK concentration‐time profiles for acetaminophen. Lines represent locally weighted scatter smoothing (LOESS).

Figure 2

Visual predicted check — final population pk model.

Figure 3

Final population PK model goodness of fit.

Figure 4

The relationship between clearance and postmenstrual age: a sigmoidal pattern with a clearance plateau of 18.9 L/h per 70 kg observed in neonates, infants, children, and adolescents.

Figure 5

Probability of avoiding opioid rescue medication versus time — active (intravenous acetaminophen) versus placebo groups by prerandomization opioid level.

Figure 6

(A) Relationship between total opioid rescue medication and different treatment intervals (ie, 0–6, 0–12, 0–18, and 0–24 hours) with linear regression results. (B) Relationship between and pain intensity difference 1 hour postdose and concentration of acetaminophen in plasma/blood and effect compartments 1 hour postdose with linear regression results by score scale.

Figure 6

(A) Relationship between total opioid rescue medication and different treatment intervals (ie, 0–6, 0–12, 0–18, and 0–24 hours) with linear regression results. (B) Relationship between and pain intensity difference 1 hour postdose and concentration of acetaminophen in plasma/blood and effect compartments 1 hour postdose with linear regression results by score scale.