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Title Meta-Analysis of Tumour Necrosis Factor-(alfa) Inhibitor Treatment for Rheumatoid Arthritis
Author Hollensen, Christian (Department of Informatics and Mathematical Modeling, Technical University of Denmark, DTU, DK-2800 Kgs. Lyngby, Denmark)
Supervisor Brockhoff, Per B. (Mathematical Statistics, Department of Informatics and Mathematical Modeling, Technical University of Denmark, DTU, DK-2800 Kgs. Lyngby, Denmark)
Institution Technical University of Denmark, DTU, DK-2800 Kgs. Lyngby, Denmark
Thesis level Master's thesis
Year 2009
Abstract Rheumatoid arthritis (RA) is a painful and disabling disease which aects 1 % of the general population. In the last decade new biologic disease-modifying antirheumatic drugs (DMARDs) have emerged, which target specic cytokines or cells, that are critical for the persistence of RA symptoms. Among these biologic drugs, three tumour necrosis factor- (TNF-) inhibitors called adalimumab, etanercept, and in iximab have been the rst to be applied in clinical practice. Though these three drugs target the same cytokine they dier by dosage, pharmacokinetic (PK) and pharmacodynamic (PD) properties. So far no meta-analyses of the drugs, which employ the efficacy time course of these three drugs or compare the efficacy of the drugs with their respective PK and PD properties, have ever been performed. A literature review was executed to nd all double-blind randomised controlled trials (DBRCTs) with the three TNF- inhibitors. Numbers of responders according to the American College of Rheumatology(ACR) response criteria were extracted from all the found publications concerning trials. A meta-analysis was performed on this data to acquire the typical efficacy progression of the three drugs at dierent dosages. Nonlinear mixed-eects modelling was employed to estimate xed parameters for the three treatments. A model with binomial distributed error and random eects on trial level was chosen as a nal model for the ACR data. A PK-PD analysis was performed for the three drugs. This analysis was based on PK data and PD parameters found from publications. Using this information, a 6-compartment PK-PD models was constructed for each of the three TNF- inhibitors. The PK-PD models concern the concentrations of TNF-, its inhibitor, and their joint complex in the body when subjected to TNF- treatment by any of the three drugs. These models were used to simulate the typical TNF- concentration in response to treatment with any of the three drugs at the dosage levels seen in the DBRCTs. The nal ACR model showed that there was a signicant dierence between the efficacy parameters of etanercept and the two other treatments, adalimumab and in iximab. Etanercept had a higher number of responders according to the parameters of the nal model. Initiation of methotrexate (MTX) treatment was shown to increase the number of responders. A termination of MTX treatment decreased the number of responders. The PK-PD model simulations displayed a concentration dierence of free TNF- between the three dierent drug treatments. The outcome of the PK-PD simulations was compared with the parameters of ACR model. This comparison showed a semilogarithmic relationship between the maximal concentration of free TNF- and the maximum proportion of responders during treatment with TNF- inhibitors. Etanercept is the TNF- treatment for RA with the highest proportion of responders. This analysis shows that the number of responders is induced by the dosage and PD characteristics of the drug. The efficacy of a TNF- treatment is determined by its ability to persistently keep TNF- concentration low.
Imprint Technical University of Denmark (DTU) : Kgs. Lyngby, Denmark
Series IMM-M.Sc.-2009-19
Original PDF ep09_19.pdf (2.70 MB)
Admin Creation date: 2009-03-31    Update date: 2012-01-17    Source: dtu    ID: 240850    Original MXD