M Valle, M Yritia, R Antonijoan, G Urbano, MR Ballester, MJ Barbanoj
Centro de Investigación de Medicamentos, Institut de Recerca del HSCSP, Departamento de FarmacologÃa y Terapéutica, Universidad Autónoma de Barcelona, Barcelona, Spain.
Introduction: A commonly described situation for benzodiazepines (BZD) is the tolerance development after chronic administration. However, although many investigators have pay attention to the possible development of acute tolerance, due to the employed methodology for data analysis, it is not clear whether all the BZD-GABAa agonists develop tolerance after a single oral dose.
Aim: To test and compare the tolerance development pattern after single oral doses of different BZD-GABAa agonists administered to healthy volunteers, when evaluating the relative alpha and relative beta activities of the EEG as pd measures.
Methodology: Data from two different studies were combined during the analysis. In the first study a single oral dose of placebo, lorazepam (4 mg) or zolpidem (20 mg) were administered randomly, in a double- blind study to 36 volunteers. In the second study alprazolam (2 mg) was administered as single oral dose to 24 healthy volunteers. In both studies different blood samples were withdrawn to determine plasma levels of the different drugs, and 16 leads EEG was measured at different times before and after drug administration. The variables derived from EEG were relative alpha (7.5-13 Hz) and relative beta (13-30 Hz). Data analysis was performed in two steps: first pharmacokinetics was analyzed using NONMEM V with FOCE interaction. The individual predicted plasma concentrations were used for the development of the pharmacodynamic model using the FO option, in the second step.
Results: A two compartmental model with first order absorption and elimination from the central compartment best described the lorazepam pK profiles including weight as covariates in volume of the central compartment and plasma clearance, whereas a one compartmental model with first- order absorption and elimination best described alprazolam and zolpidem PK profiles. None of the other studied covariates except the mentioned one, were found to influence any of the parameters.
For the PD a sigmoidal inhibitory model (relative alpha) and a sigmoidal stimulatory model (relative beta) best described the PD profiles of alprazolam and lorazepam. Different values of Imax, IC50, Emax and EC50 were estimated for each of the drugs. Tolerance was only found for zolpidem and it was best described assuming the formation of a metabolite with antagonistic properties.
Conclusions: : Acute tolerance development after single oral dose is not present for the non-selective BZD-GABAa agonists alprazolam and lorazepam, whereas a clear acute tolerance is developed in the same situation when zolpidem, a selective BZD-GABAa, agonist is used.
Reference: PAGE 13 (2004) Abstr 528 [www.page-meeting.org/?abstract=528]
Poster: poster