Population pharmacokinetic modelling of tramadol with application of the NPEM algorithms

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Abstract
Although the kinetic behaviour of tramadol has been described, the present study is the first to our knowledge, to report specifically on the population pharmacokinetic modelling of tramadol hydrochloride. The parametric Iterative Two-stage Bayesian Population Model (IT2B) program followed by the Non-parametric Expectation Maximization Population Model (NPEM2) program was used to determine population pharmacokinetic parameter values of tramadol in 138 postoperative orthopaedic Malaysian patients. All patients had received a 100 mg intravenous dose of tramadol, infused over 2-3 min, as their first postoperative analgesic. Blood was sampled at 0 min and subsequently at 15, 30 min, 1, 2, 4, 8, 16, 20 and 24 h for serum tramadol high-performance liquid chromatography analysis. The one-compartmental model pharmacokinetic parameters--volume of distribution (Vd), elimination rate constant (kel) and the total clearance rates (ClT)--found were: mean Vd = 167.6 +/- 63.84 L; median Vd = 161.48 L; mean kel = 0.1241 +/- 0.056 h(-1); median kel = 0.1138 h(-1); ClT = 19.57 +/- 9.51 L/h; median ClT =18.12 L/h. The interindividual coefficient of variation of ClT (48.56%) was higher than that of Vd (38.09%), indicating the presence of other possible influencing factors on tramadol's ClT such as CYP2D6 polymorphism, gender and age. Overall, NPEM2 suggested more diversity in the population than did IT2B.