title: Population pharmacokinetic modeling of hydromorphone in cardiac surgery patients during postoperative pain therapy.
abstract: BACKGROUND
  Hydromorphone is a µ-selective opioid agonist used in postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of hydromorphone in cardiac surgery patients during postoperative analgesia with target-controlled infusion and patient-controlled analgesia.
  
  
  METHODS
  In this study, 50 adult patients were enrolled to receive intravenous hydromorphone during postoperative pain therapy. Arterial plasma samples were collected for measurements of drug concentration. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. Results were validated and simulations were carried out to evaluate results.
  
  
  RESULTS
  Data from 49 patients (age range, 40-81 yr) were analyzed. The pharmacokinetics of hydromorphone were best described by a three-compartment model. Age was incorporated as a significant covariate for elimination clearance and central volume of distribution. Scaling all parameters with body weight improved the model significantly. The final estimates of the model parameters for the typical adult patient (67 yr old, weighing 70 kg) undergoing cardiac surgery were as follows: CL1 = 1.01 l/min, V1 = 3.35 l, CL2 = 1.47 l/min, V2 = 13.9 l, CL3 = 1.41 l/min, and V3 = 145 l. The elimination clearance decreased by 43% between the age of 40 and 80 yr, and simulations demonstrated that context-sensitive half-time increased from 26 to 84 min in 40- and 80-yr-old subjects, respectively.
  
  
  CONCLUSIONS
  The final pharmacokinetic model gave a robust representation of hydromorphone pharmacokinetics. Inclusion of age and body weight to the model demonstrated a significant influence of these covariates on hydromorphone pharmacokinetics. The application of this patient-derived population model in individualized pain therapy should improve the dosing of hydromorphone in patients undergoing cardiac surgery.
authors: From the Department of Anesthesiology, University of Erlangen-Nuremberg, Erlangen, Germany.
authors: Christian
authors: C
authors: Jeleazcov
authors: Teijo I
authors: TI
authors: Saari
authors: Harald
authors: H
authors: Ihmsen
authors: Jan
authors: J
authors: Mell
authors: Katharina
authors: K
authors: Fröhlich
authors: Ljubica
authors: L
authors: Krajinovic
authors: Jörg
authors: J
authors: Fechner
authors: Jürgen
authors: J
authors: Schüttler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D016058:Analgesia, Patient-Controlled; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006348:Cardiac Surgical Procedures; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004347:Drug Interactions; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D004091:Hydromorphone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D036502:Infusions, Intralesional; D008297:Male; D008875:Middle Aged; D010149:Postoperative Pain / Q000188:drug therapy* / Q000378:metabolism*; D011446:Prospective Studies; D015203:Reproducibility of Results; D016037:Single-Blind Method; D017409:Sufentanil / Q000008:administration & dosage / Q000627:therapeutic use; D013908:Thoracotomy
chemical_list: D000701:Analgesics, Opioid; D017409:Sufentanil; D004091:Hydromorphone