Acetaminophen pharmacokinetics in severely obese adolescents and young adults

Abstract

Background Intravenous acetaminophen is commonly administered as an adjunctive to opioids during major surgical procedures, but neither the correct pharmacokinetic size descriptor nor the dose is certain in severely obese adolescents undergoing bariatric surgery. Methods Adolescents, 14‐20 years of age, with a body mass index (BMI) ≥95th percentile for age and sex or BMI ≥40 kg·m−2, presenting for laparoscopic or robotic assisted or vertical sleeve gastrectomy were administered intravenous acetaminophen (1000 mg) following completion of the surgical procedure. Venous blood was drawn for acetaminophen assay at eight time points, starting 15 minutes after completion of the infusion and up to 12 hours afterward. Time‐concentration data profiles were analyzed using nonlinear mixed effects models. Parameter estimates were scaled to a 70‐kg person using allometry. Normal fat mass was used to assess the impact of obesity on pharmacokinetic parameters. Results The study cohort comprised 11 female patients, age 17 SD 2 years with a weight of 125 SD 19 kg and a mean BMI of 46 SD 5 kg·m−2. The plasma acetaminophen serum concentration was 17 (SD 4) μg·mL−1 at 10‐20 minutes after completion of the infusion and 5 (SD 6) μg·mL−1 at 80‐100 minutes. A two‐compartment model, used to investigate pharmacokinetics, estimated clearance 10.6 (CV 72%) L·h·70 kg−1, intercompartment clearance 37.3 (CV 63%) L·h·70 kg−1, central volume of distribution 20.4 (CV 46%) L·70 kg−1, and peripheral volume of distribution 16.8 (CV 42%) L·70 kg−1. Clearance was best described using total body weight. Normal fat mass with a parameter that accounts for fat mass contribution (Ffat) of 0.88 best described volumes. Conclusion Current recommendations of acetaminophen to a maximum dose of 1000 mg resulted in serum concentrations below detection limits in all patients within 2 hours after administration. Dose is better predicted using total body mass with allometric scaling.

Practical Challenges—Use of Paracetamol in Children and Youth Who are Overweight or Obese: A Narrative Review

“…One study enrolled male children and adolescents aged 10–17 years with nonalcoholic fatty liver disease (NAFLD) [ 29 ]. The other (single-arm) study enrolled female adolescents aged 14–20 years with morbid obesity [ 26 ]. Therefore, meaningful comparisons could not be made between the pharmacokinetic properties of paracetamol in general populations of overweight/obese versus normal-weight children and adolescents.…”

“…In a single-arm clinical trial, Hakim and colleagues [ 26 ] evaluated the pharmacokinetics of a single dose of paracetamol 1000 mg in 11 female adolescents with morbid obesity (mean BMI = 46 kg/m 2 , standard deviation 5 kg/m 2 ) aged 14–20 years. Observed data and simulated pharmacokinetic modeling demonstrated that a two-compartment model using allometric scaling provided the best fit to the observed data.…”

“…Simulations based on various paracetamol doses administered to a non-obese (50-kg) adolescent and one with morbid obesity (125 kg) showed that a paracetamol dose of 2250 mg would be required for an obese adolescent to achieve serum and effect site paracetamol concentrations comparable to those achieved by a non-obese adolescent receiving a 1000-mg dose. The dose that achieved a target concentration of 10 mg/L in the effect compartment at 2 h after administration was better predicted based on total body weight using allometric scaling than using linear models [ 26 ]. These results are consistent with the nonlinear relationship between total body weight and clearance, and the effects of fat mass on volume of distribution.…”

“…These results are consistent with the nonlinear relationship between total body weight and clearance, and the effects of fat mass on volume of distribution. Although these data suggest that dosing based on allometric scaling may improve therapeutic benefit in adolescents with morbid obesity, the increased dosage required for such individuals may increase the risk of overdose and hepatotoxicity [ 26 ].…”

Dosing Common Medications in Hospitalized Pediatric Patients with Obesity: A Review

“…Intravenous (IV) acetaminophen has a role in managing fever and postoperative pain, in order to minimize or avoid opiates. Hakim et al (20) recruited 11 adolescent girls with severe obesity and administered a single 1,000‐mg IV dose following bariatric surgery. Subsequent serum acetaminophen concentrations, < 30 µmol/L (4.5 µg/mL), were inadequate for analgesia.…”