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

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Abstract

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.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

SUV: :

Standardized uptake value

HAB: :

High-affinity binders

MAB::

Mixed-affinity binders

LAB::

Low-affinity binders

BMI: :

Body Mass Index

TSPO: :

18-KDa translocator protein

TACs:

Time-activity curves

AUC:

Area under the curve

VT::

Total volume of distribution

PBIF::

Population-based input function

IDIF::

Image-derived input function

VOI::

Volume of interest

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Acknowledgements

We would like to thank all study participants and the staff at the SHFJ PET for their assistance : Claude Comtat, Vincent Brulon, Christine Baron, Christine Coulon, Stéphane Demphel, Maud Goislard, Françoise Hinnen, Thierry Lekieffre, Christine Manciot.

Funding

PET imaging studies: Imabio3: French Health Ministry (PHRC- 0054-N 2010) and Institut Roche de Recherche et Medecine Translationelle, European Union’s Seventh Framework Programme (FP7/2007–2013), grant agreement HEALTH-F2-2011–278850 (INMiND); Inflapark: France Parkinson (GAO 2008) and Neuratris; Inflasep: ANR grant MNP2008-007125; Epitep: French Federation for Epilepsy Research.

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Authors and Affiliations

  1. Université Paris Saclay, INSERM, CNRS, CEA, Laboratoire d’Imagerie Biomedicale Multimodale (BioMaps), Service Hospitalier Frédéric Joliot, 4 Place du Général Leclerc, F-91401, ORSAY, France

    MA Peyronneau, B Kuhnast, D-L Nguyen, B Jego, G Sayet, F Caillé, P Gervais, M Sarazin, V Bouilleret, C Leroy & M. Bottlaender

  2. Laboratoire Des Maladies Neurodégénératives, Université Paris-Saclay, CEA, CNRS, MIRCen, F-92265, Fontenay-Aux-Roses, France

    S Lavisse & P Remy

  3. Sorbonne Université, UPMC Paris 06, Institut du Cerveau et de La Moelle Epinière, Hôpital de La Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, Paris, France

    B Stankoff

  4. Service de Neurologie de La Mémoire Et du Langage, GHU Paris Psychiatrie & Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France

    M Sarazin

  5. Centre Expert Parkinson, Neurologie, Hôpital Henri Mondor, AP-HP, F-94010, Créteil, France

    P Remy

  6. Université Paris-Est Créteil, INSERM U955, Institut Mondor de Recherche Biomédicale, Equipe NeuroPsychologie Interventionnelle, F-94010, Créteil, France

    P Remy

  7. Département d’Etudes Cognitives, École Normale Supérieure, Université PSL, F-75005, Paris, France

    P Remy

  8. Service de Neurophysiologie Clinique et d’Epileptologie, Hôpital Bicêtre, AP-HP, Université Paris Saclay, F-94270, Le Kremlin-Bicêtre, France

    V Bouilleret

  9. Université Paris Saclay, UNIACT, Neurospin, CEA, Gif-Sur-Yvette, F-91190, France

    M. Bottlaender

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  1. MA Peyronneau
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Contributions

This manuscript has been seen and approved by all authors, and each author has contributed significantly to this work. Subject recruitment and/or supervision and design the PET study: MB, MS, BS, SL, PR, VB, CL. Supervision and design of the metabolism and pharmacokinetic study: MAP. Statistical analysis: MAP, MB, CL; [18F]DPA-714 PK data: BJ, MAP; Radiochemistry/radiopharmacy: BK, FC, PG; WB PET images analysis: DLN, SG; MB; Brain PET images analysis: CL, MB; Manuscript draft: MAP, MB.

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Correspondence to MA Peyronneau.

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Peyronneau, M., Kuhnast, B., Nguyen, DL. et al. [18F]DPA-714: Effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function. Eur J Nucl Med Mol Imaging 50, 3251–3264 (2023). https://doi.org/10.1007/s00259-023-06286-1

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