AJP - Endocrinology and Metabolism, Vol 271, Issue 4 E775-E787, Copyright © 1996 by American Physiological Society
Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide
K. E. Fattinger, D. Verotta, H. C. Porchet, A. Munafo, J. Y. Le Cotonnec and L. B. Sheiner
Department of Pharmacy, School of Medicine, University of California, San Francisco 94143-0626, USA.
A pharmacodynamic analysis of the input-response relationship between the
gonadotropin-releasing hormone antagonist antide and luteinizing hormone
(LH) and testosterone concentrations is presented. A control compartmental
model is developed using pharmacokinetic and pharmacodynamic data from
experiments in which different short intravenous antide infusions were
given to healthy male volunteers. Because of the control interdependence
between serum LH and testosterone a separation principle similar to one we
have used previously to analyze physiological pharmacokinetic data is used
for model exploration: testosterone and LH are first modeled separately,
conditioning on the other observed response. This reveals that the LH
effect on testosterone depends on previous LH exposure and that LH depends
not on current but on previous testosterone exposure, resulting in an LH
overshoot after antide-induced suppression. Both submodels are combined
into one global model, which in addition includes a model for testosterone
circadian variation. This model describes the data well and can be used to
predict responses for some nonstudied antide dosages. However, the
sensitivity of predictions to model assumptions limits the range of valid
extrapolation, and this, too, is illustrated.
