Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide

被引:25
作者
Fattinger, KE
Verotta, D
Porchet, HC
Munafo, A
leCotonnec, JY
Sheiner, LB
机构
[1] UNIV CALIF SAN FRANCISCO, DEPT PHARM & PHARMACEUT CHEM, SCH MED, SAN FRANCISCO, CA 94143 USA
[2] UNIV CALIF SAN FRANCISCO, DEPT BIOSTAT & EPIDEMIOL, SCH MED, SAN FRANCISCO, CA 94143 USA
[3] UNIV CALIF SAN FRANCISCO, DEPT LAB MED, SCH MED, SAN FRANCISCO, CA 94143 USA
[4] UNIV ZURICH HOSP, DEPT INTERNAL MED, DIV CLIN PHARMACOL & TOXICOL, CH-8091 ZURICH, SWITZERLAND
[5] ARES SERONO, CH-1202 GENEVA, SWITZERLAND
来源
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM | 1996年 / 271卷 / 04期
关键词
gonadotropin-releasing hormone antagonist; compartmental control system; luteinizing hormone;
D O I
10.1152/ajpendo.1996.271.4.E775
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 CH 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 range of valid extrapolation, and this, too, is limits the illustrated.
引用
收藏
页码:E775 / E787
页数:13
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