Teijo I Saari (1), Harald Ihmsen (1), Jan Mell (1) , Katharina Fröhlich (1) , Jörg Fechner (1), Jürgen Schüttler (1), Christian Jeleazcov (1)
Department of Anesthesiology, University of Erlangen-Nuremberg, Germany
Objectives: Hydromorphone (HM) is an opioid analgesic used to relieve moderate-to-severe pain. The pharmacokinetic models published so far [1] consider young healthy volunteers but not postoperative patients. On the other hand, as the drug effect is dependent on the unbound plasma drug concentrations, an alteration in the protein binding during postoperative care may result in clinically significant changes in the pharmacokinetics. Therefore, we investigated the pharmacokinetics of free HM in cardiac surgery patients during postoperative pain therapy.
Methods: After IRB approval, written informed consent was obtained from 50 patients with ASA physical status class 3 undergoing coronary artery bypass surgery. HM was administered postoperatively on the ICU as target controlled infusion (TCI) with the pharmacokinetic model described by Westerling et al. [1] and plasma target concentrations of HM between 0.8 and 10 ng/ml. Arterial blood samples were drawn in each patient during and up to 12 h after TCI. The plasma concentrations of free HM were measured after ultrafiltration by LC/MS/MS [2]. A pharmacokinetic model was determined by non-linear mixed-effects modelling (FOCEI) in NONMEM 7.2 using linear multicompartment models. The influence of demographic and clinical characteristics on the elimination clearance and volumes of distribution were tested.
Results: 49 patients (40-81 yrs) received HM and data from 44 patients were analysed. Median free fraction was 0.90 with a range of 0.37 – 0.98. The pharmacokinetics of free HM were best described by a three compartment model (median PE=-4.5%). The elimination clearance CL1 and the central volume of distribution V1 decreased with age: CL1 = 16.2*(1 – 0.012*(age – 67)) mL/kg/min, V1 = 0.056*(1 – 0.0172*(age – 67)) L/kg. The intercompartmental clearances and the peripheral volumes of distribution were linearly related to body weight: CL2=20.1 mL/kg/min, V2=0.21 L/kg, CL3=22.6 mL/kg/min, V3=2.12 L/kg. The terminal half-life of HM was 186 min. No gender effect could be observed.
Conclusions: The pharmacokinetics of free HM in patients after cardiac surgery show age and weight dependent clearance and volume of distribution. Protein binding of HM in cardiac surgery patients was similar to the values reported in the literature.
References:
[1] Westerling D et al., Pain Res Manag. 1: 86-92, 1996.
[2] Saari TI et al., J. Pharmaceut Biochem Anal. 71:63-70, 2012.
Funding: This work has been supported by a grant of the German Federal Ministry of Education and Research (BMBF, FKZ 13EX1015B).
Reference: PAGE 22 () Abstr 2765 [www.page-meeting.org/?abstract=2765]
Poster: Other Drug/Disease Modelling