Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients

Abstract

Intravenous acetaminophen is a commonly used analgesic following surgery. The aims of this study were to determine the population pharmacokinetic profile of intravenous acetaminophen and its metabolites in adult surgical patients and to identify patient characteristics associated with acetaminophen metabolism in the postoperative period. 53 patients were included in the dataset; 28 were men, median age (range) 60 years (33-87), median weight (range) 74 kg (54-129). Patients received 1, 1.5 or 2 g of intravenous acetaminophen every 4-6 h. Plasma and urine samples were collected at various intervals for up to 6 days after surgery. Simultaneous modelling of parent acetaminophen and its metabolites was conducted in Phoenix(®) NLME™ to estimate pharmacokinetic parameters. The population mean estimate (CV%) for central (plasma) volume of distribution of parent acetaminophen (VC) was 13.9 (4.41) L, peripheral (tissue) volume of distribution (VT) was 50.9 (2.96) L, and intercompartmental clearance (Q) was 77.5 (9.29) L/h. The population mean (CV%) metabolic clearances for glucuronidation (CLPG) was 8.92 (3.25) L/h, sulfation (CLPS) was 0.903 (3.47) L/h, and oxidation (CLPO) was 0.533 (7.90) L/h. The population mean (CV%) urinary clearances of parent acetaminophen (CLRP) was 0.137 (5.46) L/h, acetaminophen glucuronide (CLRG) was 3.81 (6.71) L/h, acetaminophen sulfate (CLRS) was 3.13 (4.32) L/h, and acetaminophen cysteine + mercapturate (CLRO) was 3.51 (9.98) L/h. Age was found to be a significant covariate on the formation of acetaminophen glucuronide, and renal function (estimated as creatinine clearance) on the urinary excretion of acetaminophen glucuronide.

Population pharmacokinetics of intravenous acetaminophen in Japanese patients undergoing elective surgery

“…acetaminophen have been reported in different study settings. In studies of perioperative patients, age and sex [13], and age and creatinine clearance [3] were found to affect PK parameters. In a PK analysis using a pooled historical dataset from past PK studies, including not only perioperative patients but also healthy volunteers, intensive care unit patients, and perinatal women, Allegart et al [4] concluded that size, including an allometrically scaled body weight and normal fat mass (extension of the concept of predicted normal weight), and age were important covariates.…”

“…Simulations of 1 g of intravenous acetaminophen administered to patients with different body weights using the current model (a) and previous models reported by Würthwein et al[2] (b), Wang et al[6] (c), and Owens et al[3] (d). Horizontal dot lines are assumed to be the lower limit of the therapeutic range (10 μg/mL[10]) Simulations of 1 g of intravenous acetaminophen (ACET) administered to patients (weight 67 kg) over different durations using the current model.…”

“…In non-Japanese patients, some PK models of i.v. acetaminophen for adolescent [2] or adult [3,4] perioperative patients have been reported, with various factors that influence PK parameter estimates, including age [3,4], creatinine clearance [3], and body size [4]. Although the results of non-compartmental PK analysis suggest that acetaminophen administration is not prone to intrinsic ethnic differences between Japanese and non-Japanese [5], whether the PK models with compartmental structures mentioned above also predict the correct plasma drug concentrations in Japanese patients is still unknown.…”

“…The aim of this study was therefore to evaluate the predictive performances of three published PK models [2,3,6] for i.v. acetaminophen and to build a compartmental population PK model for i.v.…”

“…Acetaminophen concentration versus time on a log scale after 1 g of acetaminophen was administered intravenously over 15 min (a n = 4), 60 min (b n = 4), or 120 min (c n = 4) Measured/predicted values versus time in three different existing pharmacokinetic models reported by Würthwein et al[2] (a), Wang et al[6] (b), and Owens et al[3]. MDPE median performance error, MDAPE median absolute performance error administered over 15 min are shown in Figs.…”