A. van Rongen (1,2), M.Y. Peeters (1), D. Boerma (3), F.W. Huisman (4), B. van Ramshorst (3), H.PA. van Dongen (5), J.N. van den Anker (6,7,8), C.A.J. Knibbe (1, 2)
(1) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands. (2) Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. (3) Department of Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands. (4) Department of Oral & Maxillofacial Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands. (5) Department of Anaesthesiology and Intensive Care, St. Antonius Hospital, Nieuwegein, The Netherlands. (6) Intensive Care, Erasmus MC Sophia Children’s hospital, Rotterdam, The Netherlands. (7) Division of Clinical Pharmacology, Children’s National Medical Center, Washington DC, USA. (8) Department of Paediatric Pharmacology, University Children’s Hospital, Basel, Switzerland.
Objectives: Paracetamol is a widely used analgesic and is mainly metabolized via glucuronidation, sulphation and to a minor extent by CYP2E1, with the latter being responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially changing the safety profile of paracetamol. The aim of this study was to determine the pharmacokinetics of paracetamol and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese patients.
Methods: Twenty morbidly obese patients (mean total body weight (TBW) of 142 kg (106-193.1 kg) and mean BMI of 46.2 kg/m2 (40-55.2 kg/m2)) participated in the study. All patients received 2 gram of intravenous paracetamol. Fifteen blood samples were collected per patient until 8 hours post dose and one sample was collected at 24 hours. Population pharmacokinetic modeling and covariate analysis was performed using NONMEM. Paracetamol cysteine and mercapturate metabolites were modeled in one compartment (1).
Results: A one compartment model for paracetamol, paracetamol glucuronide, paracetamol cysteine & mercapturate and a two compartment model for paracetamol sulphate best described the data. For the glucuronide and the cysteine & mercapturate metabolites, a transit compartment model was identified to capture the delay in formation. The formation clearance of the CYP2E1-mediated cysteine & mercapturate metabolites (population mean (RSE%) of 0.0185 L/min (15%)) and central volume of distribution of paracetamol (67.1 L (3%)) increased linearly with lean body weight (p<0.001) and body weight (p<0.001), respectively. While male patients were heavier than female patients, gender was identified as covariate for the formation clearance of the glucuronide metabolite (0.356 L/min (8%) vs 0.213 L/min (5%) for male vs female, p < 0.001) and for the elimination clearance of the cysteine & mercapturate metabolite (0.57 L/min (22%) vs 0.24 L/min (17%) for male vs female, p< 0.001). No other covariates were identified (p>0.05).
Conclusions: In morbidly obese patients, a substantial influence of (lean) body weight and gender was found on the formation clearance of the CYP2E1 mediated and glucuronide metabolites and central volume of distribution of paracetamol. As these findings may potentially influence the efficacy and safety of paracetamol in morbidly obese patients, further study with inclusion of non obese individuals confirming these results, is required.
References:
[1] Owens KH, Murphy PG, Medlicott NJ, Kennedy J, Zacharias M, Curran N, et al. Population pharmacokinetics of intravenous acetaminophen and its metabolites in major surgical patients. J Pharmacokinet Pharmacodyn. 2014 Jun;41(3):211-21.
Reference: PAGE 24 () Abstr 3589 [www.page-meeting.org/?abstract=3589]
Poster: Drug/Disease modeling - Other topics