title: Exposure-response model for sibutramine and placebo: suggestion for application to long-term weight-control drug development.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Sangil
authors.initials: S
authors.lastname: Jeon
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Taegon
authors.initials: T
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Jongtae
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Soo Hyeon
authors.initials: SH
authors.lastname: Bae
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Wan-su
authors.initials: WS
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Gab-jin
authors.initials: GJ
authors.lastname: Park
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Sunil
authors.initials: S
authors.lastname: Youn
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Doo Yeon
authors.initials: DY
authors.lastname: Jang
authors.affiliation: Department of Family Medicine, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, College of Medicine, The Catholic University of Korea ; Pharmacometrics Institute for Practical Education and Training, Seoul St Mary's Hospital, Seochogu, Seoul, Republic of Korea.
authors.forename: Dong-Seok
authors.initials: DS
authors.lastname: Yim
mesh_terms: D000328:Adult; D019440:Anti-Obesity Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D003503:Cyclobutanes / Q000008:administration & dosage* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017711:Nonlinear Dynamics; D009765:Obesity / Q000188:drug therapy*; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D003503:Cyclobutanes; C058254:sibutramine
keywords: obesity; pharmacodynamics; pharmacokinetics; weight-reducing drugs