Cartographie de la diffusion tissulaire du ténofovir, de l'emtricitabine et du dolutégravir chez deux modèles animaux, la souris et le macaque cynomolgus

Since the discovery of the human immunodeficiency virus (HIV) at the origin of one of the most important pandemics of our era, research has made it possible to improve the management and prevention of HIV infection. However, this pathology, initially considered acute, has become a chronic disease due to the absence of eradiction of the virus despite antiretroviral drugs.This viral persistence could be partly the consequence of sub-therapeutic concentrations of antiretroviral drugs leading to the creation of pharmacological sanctuaries and viral reservoirs. The diffusion of antiretroviral drugs depends on the physicochemical and pharmacokinetic properties but also on the anatomical and functional characteristics of tissue, biological fluids or even HIV target cells.The main objective of this work is to map the distribution in many tissues of three antiretroviral drugs: tenofovir, emtricitabine and dolutegravir in mice (12 tissues) and cynomolgus macaques (45 tissues).Using robust, accurate, specific and sensitive analytical techniques, the different studies have made it possible to validate these animal models and the data obtained can be considered with a high level of proof.There are three main messages. The first is that there is a difference in diffusion capacity between the three antiretroviral drugs studied. Tenofovir is the one with the best potential, followed by emtricitabine and then dolutegravir. The second message is that there is a substantial difference in the permeability of different tissues for the same antiretroviral drug. Finally, the third message is that there is little variability in the diffusion of the same antiretroviral drug in the same tissue.In conclusion, these first simultaneous maps of the diffusion of three major antiretroviral drugs answer the questions of the pharmacological hypothesis on the persistence of viral replication. They will make it possible to better target the tissues of interest and to study other antiretroviral drugs with these animal models validated. These diffusion data in the virological reservoirs are thus important elements in the development of therapeutic strategies with a view to possible viral cure.Depuis la découverte du virus de l'immunodéficience humaine (VIH) à l'origine d'une des plus importantes pandémies de notre ère, la recherche a permis d'améliorer la prise en charge et la prévention de l'infection par le VIH. Cependant, cette pathologie, considérée initialement comme aiguë, est devenue une maladie chronique en raison de l'absence d'éradication du virus dans l'organisme malgré les médicaments antirétroviraux. Cette persistance virale pourrait être en partie la conséquence de concentrations infra-thérapeutiques des médicaments antirétroviraux conduisant à la création de sanctuaires pharmacologiques et de réservoirs viraux. La diffusion des médicaments antirétroviraux dépend de leurs propriétés physico-chimiques et pharmacocinétiques mais aussi des caractéristiques anatomiques et fonctionnelles des tissus, des fluides biologiques voire des cellules cibles du VIH.L'objectif principal de ce travail est d'établir la cartographie de la diffusion dans de nombreux tissus de trois médicaments antirétroviraux : ténofovir, emtricitabine et dolutégravir chez la souris (12 tissus) et le macaque cynomolgus (45 tissus).En s'appuyant sur des techniques analytiques robustes, justes, spécifiques et sensibles, les différentes études ont permis de valider ces modèles animaux et les données obtenues peuvent être considérées avec un fort niveau de preuve.Trois principaux messages se dégagent. Le premier est qu'il existe une différence de capacité de diffusion entre les trois médicaments antirétroviraux étudiés. Le ténofovir est celui avec le meilleur potentiel, suivi par l'emtricitabine puis le dolutégravir. Le deuxième message est qu'il existe une grande différence au niveau de la perméabilité des différents tissus pour un même médicament antirétroviral. Enfin, le troisième message est qu'il y a peu de variabilité quant à la diffusion d'un même médicament antirétroviral dans un même tissu.En conclusion, ces premières cartographies simultanées de la diffusion de trois médicaments antirétroviraux majeurs répondent aux questions de l'hypothèse pharmacologique sur la persistance de la réplication virale. Elles permettront de mieux cibler les tissus d'intérêt et d'étudier d'autres médicaments antirétroviraux avec ces modèles animaux validés. Ces données de diffusion dans les réservoirs virologiques sont ainsi des éléments importants dans l'élaboration des stratégies thérapeutiques en vue d'une éventuelle éradication virale

Cartographie de la diffusion tissulaire du ténofovir, de l'emtricitabine et du dolutégravir chez deux modèles animaux, la souris et le macaque cynomolgus

Since the discovery of the human immunodeficiency virus (HIV) at the origin of one of the most important pandemics of our era, research has made it possible to improve the management and prevention of HIV infection. However, this pathology, initially considered acute, has become a chronic disease due to the absence of eradiction of the virus despite antiretroviral drugs.This viral persistence could be partly the consequence of sub-therapeutic concentrations of antiretroviral drugs leading to the creation of pharmacological sanctuaries and viral reservoirs. The diffusion of antiretroviral drugs depends on the physicochemical and pharmacokinetic properties but also on the anatomical and functional characteristics of tissue, biological fluids or even HIV target cells.The main objective of this work is to map the distribution in many tissues of three antiretroviral drugs: tenofovir, emtricitabine and dolutegravir in mice (12 tissues) and cynomolgus macaques (45 tissues).Using robust, accurate, specific and sensitive analytical techniques, the different studies have made it possible to validate these animal models and the data obtained can be considered with a high level of proof.There are three main messages. The first is that there is a difference in diffusion capacity between the three antiretroviral drugs studied. Tenofovir is the one with the best potential, followed by emtricitabine and then dolutegravir. The second message is that there is a substantial difference in the permeability of different tissues for the same antiretroviral drug. Finally, the third message is that there is little variability in the diffusion of the same antiretroviral drug in the same tissue.In conclusion, these first simultaneous maps of the diffusion of three major antiretroviral drugs answer the questions of the pharmacological hypothesis on the persistence of viral replication. They will make it possible to better target the tissues of interest and to study other antiretroviral drugs with these animal models validated. These diffusion data in the virological reservoirs are thus important elements in the development of therapeutic strategies with a view to possible viral cure.Depuis la découverte du virus de l'immunodéficience humaine (VIH) à l'origine d'une des plus importantes pandémies de notre ère, la recherche a permis d'améliorer la prise en charge et la prévention de l'infection par le VIH. Cependant, cette pathologie, considérée initialement comme aiguë, est devenue une maladie chronique en raison de l'absence d'éradication du virus dans l'organisme malgré les médicaments antirétroviraux. Cette persistance virale pourrait être en partie la conséquence de concentrations infra-thérapeutiques des médicaments antirétroviraux conduisant à la création de sanctuaires pharmacologiques et de réservoirs viraux. La diffusion des médicaments antirétroviraux dépend de leurs propriétés physico-chimiques et pharmacocinétiques mais aussi des caractéristiques anatomiques et fonctionnelles des tissus, des fluides biologiques voire des cellules cibles du VIH.L'objectif principal de ce travail est d'établir la cartographie de la diffusion dans de nombreux tissus de trois médicaments antirétroviraux : ténofovir, emtricitabine et dolutégravir chez la souris (12 tissus) et le macaque cynomolgus (45 tissus).En s'appuyant sur des techniques analytiques robustes, justes, spécifiques et sensibles, les différentes études ont permis de valider ces modèles animaux et les données obtenues peuvent être considérées avec un fort niveau de preuve.Trois principaux messages se dégagent. Le premier est qu'il existe une différence de capacité de diffusion entre les trois médicaments antirétroviraux étudiés. Le ténofovir est celui avec le meilleur potentiel, suivi par l'emtricitabine puis le dolutégravir. Le deuxième message est qu'il existe une grande différence au niveau de la perméabilité des différents tissus pour un même médicament antirétroviral. Enfin, le troisième message est qu'il y a peu de variabilité quant à la diffusion d'un même médicament antirétroviral dans un même tissu.En conclusion, ces premières cartographies simultanées de la diffusion de trois médicaments antirétroviraux majeurs répondent aux questions de l'hypothèse pharmacologique sur la persistance de la réplication virale. Elles permettront de mieux cibler les tissus d'intérêt et d'étudier d'autres médicaments antirétroviraux avec ces modèles animaux validés. Ces données de diffusion dans les réservoirs virologiques sont ainsi des éléments importants dans l'élaboration des stratégies thérapeutiques en vue d'une éventuelle éradication virale

Pharmacology of Tyrosine Kinase Inhibitors: Implications for Patients with Kidney Diseases

International audienceTyrosine kinase inhibitors (TKI) have introduced a significant advancement in cancer management. These compounds are administered orally, and their absorption holds a pivotal role in determining their variable efficacy. They exhibit extensive distribution within the body, binding strongly to both plasma and tissue proteins. Often reliant on efflux and influx transporters, TKI undergo primary metabolism by intestinal and hepatic cytochrome P450 enzymes, with non-kidney clearance being predominant. Due to their limited therapeutic window, many TKI display considerable intra- and interindividual variability. This review offers a comprehensive analysis of the clinical pharmacokinetics of TKI, detailing their interactions with drug transporters and metabolic enzymes, while discussing potential clinical implications. The prevalence of kidney conditions, such as acute kidney injury (AKI) and chronic kidney disease (CKD), among cancer patients is explored in terms of their impact on TKI pharmacokinetics. Lastly, the potential nephrotoxicity associated with TKI is also examined.</jats:p

Pharmacological Validation of Long-Term Treatment with Antiretroviral Drugs in a Model of SIV-Infected Non-Human Primates

The development of animal models undergoing long-term antiretroviral treatment (ART) makes it possible to understand a number of immunological, virological, and pharmacological issues, key factors in the management of HIV infection. We aimed to pharmacologically validate a non-human primate (NHP) model treated in the long term with antiretroviral drugs after infection with the pathogenic SIVmac251 strain. A single-dose pharmacokinetic study of tenofovir disoproxil fumarate, emtricitabine, and dolutegravir was first conducted on 13 non-infected macaques to compare three different routes of administration. Then, 12 simian immunodeficiency virus (SIV)-infected (SIV+) macaques were treated with the same regimen for two years. Drug monitoring, virological efficacy, and safety were evaluated throughout the study. For the single-dose pharmacokinetic study, 24-h post-dose plasma concentrations for all macaques were above or close to 90% inhibitory concentrations and consistent with human data. During the two-year follow-up, the pharmacological data were consistent with those observed in humans, with low inter- and intra-individual variability. Rapid and sustained virological efficacy was observed for all macaques, with a good safety profile. Overall, our SIV+ NHP model treated with the ART combination over a two-year period is suitable for investigating the question of pharmacological sanctuaries in HIV infection and exploring strategies for an HIV cure

[18F]FEPPA a TSPO Radioligand: Optimized Radiosynthesis and Evaluation as a PET Radiotracer for Brain Inflammation in a Peripheral LPS-Injected Mouse Model

[18F]FEPPA is a specific ligand for the translocator protein of 18 kDa (TSPO) used as a positron emission tomography (PET) biomarker for glial activation and neuroinflammation. [18F]FEPPA radiosynthesis was optimized to assess in a mouse model the cerebral inflammation induced by an intraperitoneal injection of Salmonella enterica serovar Typhimurium lipopolysaccharides (LPS; 5 mg/kg) 24 h before PET imaging. [18F]FEPPA was synthesized by nucleophilic substitution (90 &deg;C, 10 min) with tosylated precursor, followed by improved semi-preparative HPLC purification (retention time 14 min). [18F]FEPPA radiosynthesis were carried out in 55 min (from EOB). The non-decay corrected radiochemical yield were 34 &plusmn; 2% (n = 17), and the radiochemical purity greater than 99%, with a molar activity of 198 &plusmn; 125 GBq/&micro;mol at the end of synthesis. Western blot analysis demonstrated a 2.2-fold increase in TSPO brain expression in the LPS treated mice compared to controls. This was consistent with the significant increase of [18F]FEPPA brain total volume of distribution (VT) estimated with pharmacokinetic modelling. In conclusion, [18F]FEPPA radiosynthesis was implemented with high yields. The new purification/formulation with only class 3 solvents is more suitable for in vivo studies

Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment

International audienceObjectives: The penetration of antiretroviral drugs into deep compartments, such as the CNS, is a crucial component of strategies towards an HIV cure. This study aimed to determine CSF concentrations of bictegravir, emtricitabine and tenofovir in patients with HIV-related CNS impairment (HCI) enrolled in a real-life observational study. Methods: Patients with HCI treated by optimized ART, including bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) for at least 1 month were enrolled. Plasma and CSF concentrations were measured by quality control-validated assays (LC-MS/MS). The inhibitory quotient (IQARV) was calculated as the ratio of unbound (bictegravir) or total (emtricitabine and tenofovir) concentration to half (or 90%) maximal inhibitory concentration for bictegravir (or emtricitabine and tenofovir). All numerical variables are expressed as median (range). Results: Twenty-four patients (nine women) were enrolled. The age was 45 (26-68) years. Unbound bictegravir and total emtricitabine and tenofovir CSF concentrations were 4.4 (1.6-9.6), 84.4 (28.6-337.4) and 1.6 (0.7-4.3) ng/mL, respectively. The unbound bictegravir CSF fraction was 34% (15%-82%) versus 0.33% (0.11%-0.92%) in plasma. Three patients had an IQARV above unity for the three antiretrovirals. Factors positively associated with the CSF concentration (unbound for bictegravir) were age and total plasma concentration for the three antiretrovirals. Patients aged over 51 years had higher CSF concentrations (unbound for bictegravir). Conclusions: We observed low CSF exposure to bictegravir, emtricitabine and tenofovir. These results suggest that BIC/FTC/TAF should be used with caution as first-line treatment for people living with HIV with HCI under 51 years of age

Comparison of the effect of direct-acting antiviral with and without ribavirin on cyclosporine and tacrolimus clearance values results from the ANRS CO23 CUPILT cohort

International audienc