E. Jacqz-Aigrain*, T. Debillon, P. Daoud, C. Boitras, I. Hamon, I. Rayet, M.Popon*, F. Mentré**
Pharmacologie Pédiatrique et Pharmacogénétique*, Hopital Robert Debré - Réseau de Pharmacocinétique de population en Néonatalogie (Nantes, Montreuil, Clamart, Nancy, Saint Etienne) - INSERM U436 **, Paris -France
Nalbuphine is an agonist-antagonist opioid analgesic agent administered intravenuously in critically ill neonates undergoing invasive procedures. Differences in the maturation of hepatic and renal functions currently modifying the disposition of drugs in neonates, may affect the disposition of nalbuphine, eliminated primarily by hepatic matabolism. Pharmacokinetic data are very limited and available only in adults and children over 18 months of age.
The aim of the present study was to characterize the disposition of nalbuphine in neonates and to identify the factors associated with interindividual variability. A pharmacokinetic population study was conducted in 70 neonates (40 boys) requiring intravenuous analgesia for painful procedures associated with intensive care and artificial ventilation. They received nalbuphine as bolus doses of 0.05 to 0.27mg/kg. The 137 nalbuphine concentratons obtained after the first administration of the drug were determined by HPLC and analyzed by use of NONMEM and a one compartmental model with two parameters: clearance (CL) and volume (V). The influence of birth weight (range: 680 to 4320 grams), gestational age at birth (range: 25 to 42 weeks), posnatal age (range: 1 to 21 days), diseases and comedications were investigated.
Results : Birth weigh was found to be significantly related with both CL and V. The estimates of the populationmeans and interindividual coefficients of variations in the population model including body weight was 0.50 L/kg/hr (CV: 76%) for CL and 2.24 L/kg (CV: 58%) for V. In the final population model, it was found that CL was 1.5 times higher in boys, V was 1.5 times higher in boys, 1.3 times in neonates with respiratory distress and 0.62 times lower when other pulmonary diseases were present. The interpatient CV were reduced to 73% and 50% for CL and V by the inclusion of these covariates. No influence of the other covariates tested was found, including apgar scores, biological parameters and comedications.
Conclusion : In the neonates studied, CL was slower than the values reported in older infants children and adults. Birth weigh was a major determinant among the factors of variability of nalbuphine disposition. Although the therapeutic interval remains to be determined, it is clear that the mean nalbuphine doses required for critically ill neonates are lower than those required for older infants.
Reference: PAGE 10 (2001) Abstr 191 [www.page-meeting.org/?abstract=191]
Poster: poster