[18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function.

PURPOSE: We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. METHODS: The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([18F]DPA-71470-90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann-Whitney or Kruskal-Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. RESULTS: As no significant differences were observed between arterial and venous [18F]DPA-71470-90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470-90 was not significantly different between patients and HCS (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [18F]DPA-71470-90 (up to 88% or down to 23%) and SUV70-90 values (2-threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [18F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VTIND) or population-based input function derived from untreated HCs (VTPBIF) indicated that non-considering the individual metabolism rate led to a bias of about 30% in VT values. Multiple linear regression model analysis of subjects free of these co-medications suggested significant correlations between [18F]DPA-71470-90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [18F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole-body PET/CT exhibited a high uptake of the tracer in TSPO-rich organs (heart wall, spleen, kidneys…) and those involved in metabolism and excretion pathways (liver, gallbladder) in HAB and MAB with a strong decrease in LAB (-89% and -85%) resulting in tracer accumulation in plasma (4.5 and 3.3-fold increase). CONCLUSION: Any co-medication that inhibits or induces CYP3A4 as well as TSPO genetic status, age, BMI and sex mostly contribute to interindividual variations of the radiotracer metabolism and/or concentration that may affect the input function of [18F]DPA-714 and consequently its human brain and peripheral uptake. TRIAL REGISTRATION: INFLAPARK, NCT02319382, registered December 18, 2014, retrospectively registered; IMABIO 3, NCT01775696, registered January 25, 2013, retrospectively registered; INFLASEP, NCT02305264, registered December 2, 2014, retrospectively registered; EPI-TEP, EudraCT 2017-003381-27, registered September 24, 2018.

Impact of socioeconomic status on diabetes and cardiovascular risk factors: results of a large French survey.

AIM: This study examined the association between deprivation and diabetes in a large French population, and evaluated the impact of deprivation on diabetes after taking in account a number of confounding factors. METHODS: A total of 32,435 men and 16,378 women, aged 35 to 80 years, who had a health checkup at the "Centre d'Investigations Préventives et Cliniques" (IPC Centre: a preventive medical center in Paris, France), between January 2003 and December 2006, were evaluated. Socioeconomic deprivation was assessed using the EPICES score. The most deprived subjects were those in the fifth quintile of score distribution. RESULTS: Several cardiovascular risk markers increased significantly in deprived subjects. In both genders, deprivation was associated with deleterous health status and lifestyle habits. In women, BMI, central obesity and the metabolic syndrome were associated with deprivation. The prevalence of diabetes increased with deprivation level. Compared with the first quintile of EPICES score distribution, the prevalence of diabetes was three to eight times higher in the fifth quintile. After taking into account age, and biological, clinical and lifestyle parameters, the risk of diabetes onset (odds ratio) among deprived vs. non-deprived subjects was 2.54 (95% CI: 1.99-3.24) in men and 2.2 (95% CI: 1.44-3.35) in women. CONCLUSION: In the general French population, deprivation was associated with deleterious health status and lifestyle. Risk of diabetes increased linearly with deprivation level and, after taking into account various confounding factors, the risk of diabetes remained significantly higher among deprived subjects. Other factors such as nutrition should now be examined to explain the excess risk of diabetes among the most deprived people.

Quantitative organ time activity curve extraction from rodent PET images without anatomical prior.

PURPOSE: Numerous new drug candidates fail because of inadequate pharmacokinetics. Positron emission tomography (PET) enables the noninvasive characterization of the drug in humans and animals. The aim of the present work was the comparison of methods for the extraction of organ time activity curves from rodent PET images without requiring resort to anatomical information. METHODS: The rodent organs were segmented using the local means analysis method and the accuracy of the time activity curve (TAC) estimated using four methods was compared: The mean TAC (Mean), the TAC computed in a selection of organ voxels (ROIopt), and the TAC corrected for partial volume effect using the geometric transfer matrix (GTM) method. The accuracy of the TAC estimated using the three methods was compared on phantom simulations and on experimental data sets on mice injected with fluorothymidine. RESULTS: The segmentation quality measured on phantom simulation was 80% of overlap between segmented and gold standard organs. On the phantom simulations, the error on the TAC estimation on phantom simulations was lower for ROIopt (8%) than using the GTM (18%) and the Mean (27%) methods. Similar results were achieved on the experimental data sets: ROIopt (5.8%), GTM (9.7%), and Mean (12%). CONCLUSIONS: The new ROI optimization method was fast and precise for all homogeneous organs, while mean organ TAC computation led as expected to important errors. GTM improved the quantification accuracy but showed instabilities due to segmentation errors and to small organ sizes. Partial volume effect correction or limitation is thus possible for the extraction of precise organ TACs without requiring either manual delineation or an anatomical modality.