NDLI: Exposure–response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development

Content Provider	PubMed Central
Author	Han, Seunghoon Jeon, Sangil Hong, Taegon Lee, Jongtae Bae, Soo Hyeon Park, Wan-su Park, Gab-jin Youn, Sunil Jang, Doo Yeon Kim, Kyung-soo Yim, Dong-seok
Copyright Year	2015
Abstract	No wholly successful weight-control drugs have been developed to date, despite the tremendous demand. We present an exposure–response model of sibutramine mesylate that can be applied during clinical development of other weight-control drugs. Additionally, we provide a model-based evaluation of sibutramine efficacy. Data from a double-blind, randomized, placebo-controlled, multicenter study were used (N=120). Subjects in the treatment arm were initially given 8.37 mg sibutramine base daily, and those who lost <2 kg after 4 weeks’ treatment were escalated to 12.55 mg. The duration of treatment was 24 weeks. Drug concentration and body weight were measured predose and at 4 weeks, 8 weeks, and 24 weeks after treatment initiation. Exposure and response to sibutramine, including the placebo effect, were modeled using NONMEM 7.2. An asymptotic model approaching the final body weight was chosen to describe the time course of weight loss. Extent of weight loss was described successfully using a sigmoidal exposure–response relationship of the drug with a constant placebo effect in each individual. The placebo effect was influenced by subjects’ sex and baseline body mass index. Maximal weight loss was predicted to occur around 1 year after treatment initiation. The difference in mean weight loss between the sibutramine (daily 12.55 mg) and placebo groups was predicted to be 4.5% in a simulation of 1 year of treatment, with considerable overlap of prediction intervals. Our exposure–response model, which included the placebo effect, is the first example of a quantitative model that can be used to predict the efficacy of weight-control drugs. Similar approaches can help decision-making during clinical development of novel weight-loss drugs.
Related Links	http://dx.doi.org/10.2147/dddt.s85435
Ending Page	5194
Page Count	10
Starting Page	5185
File Format	PDF
ISSN	11778881
e-ISSN	11778881
Journal	Drug Design, Development and Therapy
Volume Number	9
Language	English
Publisher	Dove Medical Press
Publisher Date	2015-09-01
Access Restriction	Open
Rights Holder	Dove Medical Press
Subject Keyword	Pharmacology Drug Discovery Pharmaceutical Science Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Pharmacology Pharmaceutical Science

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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