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

• Published in: European journal of nuclear medicine and molecular imaging Vol. 50; no. 11; pp. 3251 - 3264
• Main Authors: Peyronneau, MA, Kuhnast, B, Nguyen, D-L, Jego, B, Sayet, G, Caillé, F, Lavisse, S, Gervais, P, Stankoff, B, Sarazin, M, Remy, P, Bouilleret, V, Leroy, C, Bottlaender, M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2023; Springer Nature B.V; Springer Verlag (Germany) [1976-....]
• Subjects: Affinity; Age; Bioengineering; Blood plasma; Body mass index; Body size; Brain; Cardiology; Correlation; Females; Fluorine isotopes; Gallbladder; Imaging; Inflammation; Kruskal-Wallis test; Life Sciences; Males; Medicine; Medicine & Public Health; Metabolism; Neuroimaging; Neurological diseases; Nuclear Medicine; Oncology; Original Article; Orthopedics; Pharmacokinetics; Plasma; Polymorphism; Positron emission; Positron emission tomography; Radioactive tracers; Radiology; Regression analysis; Regression models; Sex; Sex differences; Solid phases; F]DPA-714; Positron Emission Tomography; TSPO; Neuroinflammation; [; CYP; Metabolism; [18F]DPA-714
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-023-06286-1

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-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 [ 18 F]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.