Date of Award

2000

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Pharmaceutical Sciences

First Advisor

Sara Rosenbaum

Abstract

Warfarin is widely used oral anticoagulant and its pharrnacokinetic (PK) and pharrnacodynamic (PD) properties have been extensively studied. It has a narrow therapeutic index and displays poor quality of treatment due to its complex pharmacology and wide inter and intraindividual variability in the dose-response relationship. This study developed an integrated PK-PD model using STELLA® to describe the dose concentration- effect relationship for warfarin. This model used previously reported\ population PK and PD models and parameter values to generate dose-response data. A one compartment stereo-specific semi-physiological PK model with zero-order drug input was linked to an indirect PD model describing the anticoagulant effect. The indirect PD model consisted of two components: (i) the plasma concentration of S-enantiomer of warfarin (Cs) was related to synthesis of prothrombin complex activity (PCA) described by sigmoid Imax model (ii) conversion of PCA to prothrombin time ratio (PTR), which is further standardized in terms of INR. The model was used to study the manner in which the interindividual variability in fundamental PK parameters (intrinsic clearance, protein binding affinity constant and protein concentration), PD parameters (potency and sigmoidicity) and intraindividual variability in dose affect warfarin response. For each condition of interindividual variability studied, 100 sets of PK and PD response data were collected and % coefficient of variation (CV) was calculated. For each condition of intraindividual variability studied, 2000 data sets of PD response were collected and % CV was calculated. For the model used in this study, variability in the response to warfarin was least sensitive to interindividual variability in protein binding affinity constant of S-warfarin (Ka_s), protein concentration (P) & sigmoidicity (Y) and also to intraindividual variability in dose. The PK and PD response was found to be most sensitive to interindividual variability in intrinsic clearance of S-enantiomer (CLint_s) and potency (IC5o) parameters. Clinically, these parameters are important and their variability in population must be taken into account in order to optimize the dose and use the drug effectively and safely.

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