Abstract:
:A mechanistic drug-disease model was developed on the basis of a previously published integrated glucose-insulin model by Jauslin et al. A glucokinase activator was used as a test compound to evaluate the model's ability to identify a drug's mechanism of action and estimate its effects on glucose and insulin profiles following oral glucose tolerance tests. A kinetic-pharmacodynamic approach was chosen to describe the drug's pharmacodynamic effects in a dose-response-time model. Four possible mechanisms of action of antidiabetic drugs were evaluated, and the corresponding affected model parameters were identified: insulin secretion, glucose production, insulin effect on glucose elimination, and insulin-independent glucose elimination. Inclusion of drug effects in the model at these sites of action was first tested one-by-one and then in combination. The results demonstrate the ability of this model to identify the dual mechanism of action of a glucokinase activator and describe and predict its effects: Estimating a stimulating drug effect on insulin secretion and an inhibiting effect on glucose output resulted in a significantly better model fit than any other combination of effect sites. The model may be used for dose finding in early clinical drug development and for gaining more insight into a drug candidate's mechanism of action.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Jauslin PM,Karlsson MO,Frey Ndoi
10.1177/0091270011422231subject
Has Abstractpub_date
2012-12-01 00:00:00pages
1861-71issue
12eissn
0091-2700issn
1552-4604pii
0091270011422231journal_volume
52pub_type
杂志文章,随机对照试验abstract::Few treatments for human diseases have received as much investigation in the past 20 years as probiotics. In 2017, English-language meta-analyses totaling 52 studies determined the effect of probiotics on conditions ranging from necrotizing enterocolitis and colic in infants to constipation, irritable bowel syndrome, ...
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journal_title:Journal of clinical pharmacology
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