Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/134945
Title: MODELING AND SIMULATION OF ANTI-SCLEROSTIN THERAPY FOR THE TREATMENT OF OSTEOPOROSIS
Authors: TANG CHENG CAI
Keywords: Sclerostin, pharmacokinetics, pharmacodynamics, systems pharmacology, monoclonal antibody, osteoporosis
Issue Date: 26-May-2016
Source: TANG CHENG CAI (2016-05-26). MODELING AND SIMULATION OF ANTI-SCLEROSTIN THERAPY FOR THE TREATMENT OF OSTEOPOROSIS. ScholarBank@NUS Repository.
Abstract: Osteoporosis is a degenerative bone disease characterized by low bone mineral density (BMD) and increased risk of fracture associated with higher morbidity and mortality. Current treatments for osteoporosis included antiresorptives that reduce bone turnover and halt the bone loss and anabolics that enhance bone turnover and encourage new bone formation. The majority of osteoporosis therapies are antiresorptives and there is only one type of anabolic therapy based on parathyroid hormone (PTH) analogue. Current available treatments have their limitations and there is a medical need for new anabolic bone treatment. Anti-sclerostin therapy is currently being developed as a bone anabolic treatment for degenerative bone diseases. Sclerostin is a protein produced by osteocytes which inhibits bone formation. Monoclonal antibodies (mAbs) that target and disrupt the sclerostin actions demonstrated increase in bone formation and BMD in preclinical experiments and clinical trials. The increased anabolic bone activities were not associated with elevated bone resorption, unlike PTH based therapy. This novel therapeutic mechanism is a promising new treatment option for osteoporosis. In the first part of this report, we built a population pharmacokinetic-pharmacodynamics (PK-PD) model investigating the exposure and efficacy of blosozumab. Blosozumab is a humanized mAb against sclerostin tested clinically for the treatment of osteoporosis by Eli Lilly and Company. The population PK of blosozumab was characterized by a two-compartment model with first-order absorption and both linear and saturable clearance (CL). Body weight was found to influence volume of distribution and saturable CL. The population PK-PD model was an indirect response model linked to a hypothetical target engagement module which drives up production rate of BMD. In the second part of this report, we assembled publicly available information of anti-sclerostin clinical trials and built an integrated systems biology bone remodeling model with the actions of sclerostin on osteoblast and osteoclast regulations. A target-mediated drug disposition model was first developed based on the reported PK and total sclerostin level to quantify the level of target engagement and predict the unbound sclerostin profiles. The regulatory actions of sclerostin on osteoblast and osteoclast were added to a bone remodeling model as described by Lemaire et al., 2004. Sclerostin regulate bone formation by enhancing apoptosis and repressing the maturation of active osteoblasts as well as activate osteoclast maturation. The osteoblast and osteoclast were then linked to the BMD formation and destruction rates to describe the lumbar spine and total hip BMD response. Both models were compared and used to predict and optimize dose regimens for future clinical trials. The systems biology model was used to predict clinical efficacies of a wide range of dose regimens and generate hypothesis of sclerostin regulation of bone formation. The population PK-PD model was used to quantify variability, identify potential covariates, refine the dose regimens and assess impact of patient factors on drug exposure and clinical efficacies.
URI: http://scholarbank.nus.edu.sg/handle/10635/134945
Appears in Collections:Ph.D Theses (Open)

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
TangCC.pdf5.35 MBAdobe PDF

OPEN

NoneView/Download

Page view(s)

24
checked on Jan 21, 2018

Download(s)

57
checked on Jan 21, 2018

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.