Abstract: International audience ; IntroductionMicrodosing approaches allow the administration of infra-therapeutic doses of drug candidates to humans. This approach, carried out upstream of Phase I, is referred as “Phase 0” [1]. Decisive clinical PK can therefore be obtained at a early stage compared to the traditional process. A microdose PET (positron emission tomography) study was performed in subjects to assess the role of Organic Anion-Transporting Polypeptides (OATP) for liver uptake and their impact on whole-body pharmacokinetics (WBPK), using the substrate Glyburide as a model drug [2].The aim of this work was to model the WBPK of radiolabeled glyburide (11C-glyburide) with or without pre-infusion of rifampicin, a potent inhibitor of OATPs [2].MethodsWhole-body dynamic acquisitions after injection of a microdose of 11C-glyburide were obtained in 16 healthy volunteers using a PET scanner, with repeated acquisition, over 40 minutes. PET images were reconstructed manually outlining volumes of interest (VOIs). Time-activity curves (TACs) generated by the VOIs (MBq/cc) were converted to concentrations (µg/mL). 10 subjects also underwent a second session, where injection of 11C-glyburide was preceded by an infusion of rifampicin.Using Nonlinear Mixed Effect models (NLMEM), we modelled the kinetics in 5 selected organs of importance for the distribution and elimination: arterial blood compartment (aorta + left ventricle of the heart), liver, kidneys, pancreas and spleen .The structural model was built using the data from 11C-glyburide administered alone. Each organ was first modelled separately using standard compartment models, to obtain initial parameter estimates. Models were then fitted simultaneously for all 5 organs, investigating for each organ the number of compartments, linear and non-linear rate constants for distribution and elimination, and finally the residual error model. Model selection was based on the Bayesian Information Criterion (BIC). For organs which showed rapid distribution, a simple ratio of ...
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