title: Population pharmacokinetic modelling of tramadol using inverse Gaussian function for the assessment of drug absorption from prolonged and immediate release formulations.
abstract: This study aimed to develop a population pharmacokinetic model for tramadol that combines different input rates with disposition characteristics. Data used for the analysis were pooled from two phase I bioavailability studies with immediate (IR) and prolonged release (PR) formulations in healthy volunteers. Tramadol plasma concentration-time data were described by an inverse Gaussian function to model the complete input process linked to a two-compartment disposition model with first-order elimination. Although polymorphic CYP2D6 appears to be a major enzyme involved in the metabolism of tramadol, application of a mixture model to test the assumption of two and three subpopulations did not reveal any improvement of the model. The final model estimated parameters with reasonable precision and was able to estimate the interindividual variability of all parameters except for the relative bioavailability of PR vs. IR formulation. Validity of the model was further tested using the nonparametric bootstrap approach. Finally, the model was applied to assess absorption kinetics of tramadol and predict steady-state pharmacokinetics following administration of both types of formulations. For both formulations, the final model yielded a stable estimate of the absorption time profiles. Steady-state simulation supports switching of patients from IR to PR formulation.
authors.affiliation: Krka, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo Mesto, Slovenia.
authors.forename: Nina
authors.initials: N
authors.lastname: Brvar
authors.affiliation: Krka, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo Mesto, Slovenia.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Mateović-Rojnik
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia. Electronic address: iztok.grabnar@ffa.uni-lj.si.
authors.forename: Iztok
authors.initials: I
authors.lastname: Grabnar
mesh_terms: D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008954:Models, Biological; D011110:Polymorphism, Genetic; D014147:Tramadol / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6
keywords: Absorption; Inverse Gaussian function; Population pharmacokinetics; Steady state; Tramadol