Models of tolerance are commonly derived on empirical grounds, because of l
ack of knowledge about the mechanism of tolerance or because of the difficu
lty of appropriately simplifying complex physiological processes. The prese
nt study was performed to evaluate the interchangeability of tolerance mode
ls used in the literature and to address some determinants for selection of
an appropriate design and data analysis strategy.
Seven models were chosen (noncompetitive antagonist model, partial agonist
model, reverse agonist model, direct moderator model, indirect moderator mo
del, pool model and adaptive pool model) along with their corresponding par
ameter estimates, representing a wide range of empirical models.
The performance of the models on various data sets was evaluated. Data were
simulated from each original model and were further analysed by the other
models. The effect-time course of each and every data set could be describe
d well by at least 2 different empirical tolerance models, but no model cou
ld describe all the data sets adequately. However, all models could adequat
ely describe at least 2 different data sets. This indicates that, without a
dditional knowledge or assumptions. it is unlikely that reliable mechanisti
c information can be deduced from the mere fact that 1 (or more) of these m
odels can describe the data. Generally, data expressing only limited tolera
nce can be described by a wide variety of models. whereas few models will b
e appropriate for data characterised hy extensive tolerance.
The models that pave an adequate description of a data set were selected fo
r further study that investigated their predictive capacity based on the pa
rameters previously determined. Predictions were made for 4 different admin
istration schemes. The selected models gave similar predictions for the ext
ended designs of 3 data sets for which the original study designs character
ised tolerance well. For the other 4 data sets, the selected models gave di
sparate predictions, although the models described the original data set we
ll. Thus, the predictive capability of a model was linked to the original s
tudy design, whereas the correlation between predictive performance and the
type of model was weak or absent. Based on the results. factors of importa
nce for the design and evaluation of studies of tolerance were identified a
nd discussed.