title: Limited-sampling strategy models for estimating the pharmacokinetic parameters of 4-methylaminoantipyrine, an active metabolite of dipyrone.
abstract: Bioanalytical data from a bioequivalence study were used to develop limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) and the peak plasma concentration (Cmax) of 4-methylaminoantipyrine (MAA), an active metabolite of dipyrone. Twelve healthy adult male volunteers received single 600 mg oral doses of dipyrone in two formulations at a 7-day interval in a randomized, crossover protocol. Plasma concentrations of MAA (N = 336), measured by HPLC, were used to develop LSS models. Linear regression analysis and a "jack-knife" validation procedure revealed that the AUC(0-infinity) and the Cmax of MAA can be accurately predicted (R2>0.95, bias <1.5%, precision between 3.1 and 8.3%) by LSS models based on two sampling times. Validation tests indicate that the most informative 2-point LSS models developed for one formulation provide good estimates (R2>0.85) of the AUC(0-infinity) or Cmax for the other formulation. LSS models based on three sampling points (1.5, 4 and 24 h), but using different coefficients for AUC(0-infinity) and Cmax, predicted the individual values of both parameters for the enrolled volunteers (R2>0.88, bias = -0.65 and -0.37%, precision = 4.3 and 7.4%) as well as for plasma concentration data sets generated by simulation (R2>0.88, bias = -1.9 and 8.5%, precision = 5.2 and 8.7%). Bioequivalence assessment of the dipyrone formulations based on the 90% confidence interval of log-transformed AUC(0-infinity) and Cmax provided similar results when either the best-estimated or the LSS-derived metrics were used.
authors.affiliation: Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, CPQ, Praça da Cruz Vermelha, 23, 20130-230 Rio de Janeiro, RJ, Brazil. kurtz@inca.org.br
authors.forename: G
authors.initials: G
authors.lastname: Suarez-Kurtz
authors.forename: F M
authors.initials: FM
authors.lastname: Ribeiro
authors.forename: R C
authors.initials: RC
authors.lastname: Estrela
authors.forename: F L
authors.initials: FL
authors.lastname: Vicente
authors.forename: C J
authors.initials: CJ
authors.lastname: Struchiner
mesh_terms: D000328:Adult; D019540:Area Under Curve; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004177:Dipyrone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D047069:Pyrazolones; D013810:Therapeutic Equivalency
chemical_list: D047069:Pyrazolones; D004177:Dipyrone; C008667:noramidopyrine