[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 [ 18 F]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 [ 18 F]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 ([ 18 F]DPA-714 70–90 ) and corresponding normalized plasma concentration (SUV 70-90 ) 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 [ 18 F]DPA-714 at equilibrium was investigated. Results As no significant differences were observed between arterial and venous [ 18 F]DPA-714 70–90 and SUV 70-90 , venous plasma was used for correlations. [ 18 F]DPA-714 70–90 was not significantly different between patients and HC S (59.7 ± 12.3% vs 60.2 ± 12.9%) despite high interindividual variability. However, 47 subjects exhibiting a huge increase or decrease of [ 18 F]DPA-714 70–90 (up to 88% or down to 23%) and SUV 70-90 values (2–threefold) were found to receive co-medications identified as inhibitors or inducers of CYP3A4, known to catalyse [ 18 F]DPA-714 metabolism. Comparison between cortex-to-plasma ratios using individual input function (VT IND ) or population-based input function derived from untreated HCs (VT PBIF ) 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 [ 18 F]DPA-714 70–90 and age, BMI and sex while TSPO polymorphism did not influence the metabolism of the radiotracer. [ 18 F]DPA-714 metabolism fell with age and BMI and was significantly faster in females than in males. Whole