Abstract
Introduction
Intravenous (i.v.) acetaminophen is administered during surgery for postoperative analgesia. However, little information is available on the pharmacokinetics of i.v. acetaminophen in Japanese patients undergoing surgery under general anesthesia.
Methods
The study was approved by the Institutional Review Board and registered at UMIN-CTR (UMIN000013418). Patients scheduled to undergo elective surgery under general anesthesia were enrolled after obtaining written informed consent. During surgery, 1 g of i.v. acetaminophen was administered over 15, 60, or 120 min. Acetaminophen concentrations (15 or 16 samples per case) were measured at time points from 0−480 min after the start of administration (liquid chromatography−mass spectrometry/tandem mass spectrometry; limit of quantitation 0.1 μg/mL). The predictive performance of three published pharmacokinetic models was evaluated. Population pharmacokinetics were also analyzed using a nonlinear mixed-effect model based on the NONMEM program.
Results
Data from 12 patients who underwent endoscopic or lower limb procedures were analyzed (male/female = 7/5, median age 55 years, weight 63 kg). Anesthesia was maintained with remifentanil and propofol or sevoflurane. The pharmacokinetic model of i.v. acetaminophen reported by Würthwein et al. worked well. Using 185 datapoints, the pharmacokinetics of i.v. acetaminophen were described by a two-compartment model with weight as a covariate but not age, sex, or creatinine clearance. The median prediction error and median absolute prediction error of the final model were −1 and 10%, respectively.
Conclusion
A population pharmacokinetic model of i.v. acetaminophen in Japanese patients was constructed, with performance within acceptable ranges.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Japan Ministry of Health LaW. National Health and Nutrition Survey. 2014. http://www.e-stat.go.jp/SG1/estat/GL08020103.do?_toGL08020103_&listID=000001151595&requestSender=estat. Accessed 29 June 2016
Wurthwein G, Koling S, Reich A, Hempel G, Schulze-Westhoff P, Pinheiro PV, Boos J. Pharmacokinetics of intravenous paracetamol in children and adolescents under major surgery. Eur J Clin Pharmacol. 2005;60:883–8.
Owens KH, Murphy PG, Medlicott NJ, Kennedy J, Zacharias M, Curran N, Sreebhavan S, Thompson-Fawcett M, Reith DM. Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients. J Pharmacokinet Pharmacodyn. 2014;41:211–21.
Allegaert K, Olkkola KT, Owens KH, Van de Velde M, de Maat MM, Anderson BJ. Covariates of intravenous paracetamol pharmacokinetics in adults. BMC Anesthesiol. 2014;14:77.
Kumagai Y, Endo Y. Comparison of pharmacokinetic of intravenous acetaminophen between Japanese and non-Japanese (in Japanese). J Clin Therap Med. 2013;29:899–907.
Wang C, Allegaert K, Tibboel D, Danhof M, van der Marel CD, Mathot RA, Knibbe CA. Population pharmacokinetics of paracetamol across the human age-range from (pre)term neonates, infants, children to adults. J Clin Pharmacol. 2014;54:619–29.
Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm. 1992;20:63–94.
Bonate P. Nonlinear mixed effects models: theory. Pharmacokinetic-pharmacodynamic modeling and simulation. Springer; 2010. p. 205–65.
Sepulveda P, Cortinez LI, Saez C, Penna A, Solari S, Guerra I, Absalom AR. Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children. Br J Anaesth. 2011;107:593–600.
Anderson BJ, Holford NH, Woollard GA, Kanagasundaram S, Mahadevan M. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology. 1999;90:411–21.
Masui K, Upton RN, Doufas AG, Coetzee JF, Kazama T, Mortier EP, Struys MM. The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data. Anesth Analg. 2010;111:368–79.
Owens KH, Medlicott NJ, Zacharias M, Curran N, Chary S, Thompson-Fawcett M, Reith DM. The pharmacokinetic profile of intravenous paracetamol in adult patients undergoing major abdominal surgery. Ther Drug Monit. 2012;34:713–21.
Liukas A, Kuusniemi K, Aantaa R, Virolainen P, Niemi M, Neuvonen PJ, Olkkola KT. Pharmacokinetics of intravenous paracetamol in elderly patients. Clin Pharmacokinet. 2011;50:121–9.
Gibb IA, Anderson BJ. Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration. Arch Dis Child. 2008;93:241–7.
Singla NK, Parulan C, Samson R, Hutchinson J, Bushnell R, Beja EG, Ang R, Royal MA. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012;12:523–32.
Peeters MY, Aarts LP, Boom FA, Bras LJ, Tibboel D, Danhof M, Knibbe CA. Pilot study on the influence of liver blood flow and cardiac output on the clearance of propofol in critically ill patients. Eur J Clin Pharmacol. 2008;64:329–34.
Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S. Paracetamol: new vistas of an old drug. CNS Drug Rev. 2006;12:250–75.
Acknowledgments
We would like to acknowledge the expert assistance of Ms. Keiko Sato, MT, who helped with the processing of blood samples.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
This work was supported by JSPS KAKENHI Grant Number 15K20052.
Conflict of interest
All authors have no conflicts of interest to declare.
About this article
Cite this article
Imaizumi, T., Obara, S., Mogami, M. et al. Population pharmacokinetics of intravenous acetaminophen in Japanese patients undergoing elective surgery. J Anesth 31, 380–388 (2017). https://doi.org/10.1007/s00540-017-2358-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00540-017-2358-7