Pharmacokinetic/Pharmacodynamic Modelling of the Analgesic Effects of Tramadol in the Paediatric Population
I.F. Trocˇniz (1), M.J. Garrido (1), and F. Rombout (2)
(1) Department of Pharmacy, School of Pharmacy, University of Navarra, Pamplona, Spain and (2) Department for Modelling and Simulation, GrŘnenthal GmbH, Aachen, Germany
Introduction: The metabolite O-demethyltramadol (M1) is the main responsible for the analgesia after administration of tramadol (T). The ability of young children to form M1 is still not characterised.
Purpose: To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for T in paediatrics.
Methods: 104 children [mean age (range) = 4.55 (2-8) years; mean weight (range) = 19.65 (10-43 kg)] received postoperatively an initial 2.5 min i.v. infusion of T at 1 mg/kg. Depending on pain relief one third of the initial dose was given at 15, 30 and/or 45 min. Serum samples and several response variables related to pain relief were recorded for a 6 h period. The latter were modelled as ordered categorical variables using logistic regression in NONMEM V.
Results: PK. Disposition of T and M1 was described with a two and a one-compartment model, respectively. Weight showed significant effects (p<0.001) on T and M1 distribution and on elimination of T, respectively. Inter-subject variability did not exceed 52%. The mean (range) predicted maximum plasma concentration values for T and M1 were: 1914.7 (1067.6 - 3310) and 25 (9.7 - 87.4) ng/mL, respectively. PK/PD. M1 in the effect site was the best predictor of crying and agitation. Movement was best correlated with T in the effect site. Weight was found to have a significant (P < .05) effect on the baseline pain relief of crying and agitation. Typical steady-state plasma concentration levels of M1 and T of 10 and 120 ng.mL-1 in a 20 kg child, were associated with a 95 % probability of achieving complete pain relief.
Conclusions: T and M1 show predictable PK and both are important predictors of T induced analgesia. Children have the ability to produce enough M1 to achieve adequate pain relief safely.