New 8-nitroquinolinone derivative displaying submicromolar in vitro activities against both Trypanosoma brucei and cruzi

International audienceAn antikinetoplastid pharmacomodulation study was conducted at position 6 of the 8-nitroquinolin-2(1H)-one pharmacophore. Fifteen new derivatives were synthesized and evaluated in vitro against L. infantum, T. brucei brucei, and T. cruzi, in parallel with a cytotoxicity assay on the human HepG2 cell line. A potent and selective 6-bromo-substituted antitrypanosomal derivative 12 was revealed, presenting EC50 values of 12 and 500 nM on T. b. brucei trypomastigotes and T. cruzi amastigotes respectively, in comparison with four reference drugs (30 nM ≤ EC50 ≤ 13 μM). Moreover, compound 12 was not genotoxic in the comet assay and showed high in vitro microsomal stability (half life >40 min) as well as favorable pharmacokinetic behavior in the mouse after oral administration. Finally, molecule 12 (E° = −0.37 V/NHE) was shown to be bioactivated by type 1 nitroreductases, in both Leishmania and Trypanosoma, and appears to be a good candidate to search for novel antitrypanosomal lead compounds

Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Antikinetoplastid SAR study in 3-nitroimidazopyridine series:identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties.

International audienceTo study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = −0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program

Suivi du patient transplanté rénal traité par tacrolimus par pharmacocinétique de population et machine learning

Tacrolimus, the cornerstone of immunosuppressive therapy in solid organ transplantation, has a narrow therapeutic range and significant inter-individual variability that rapidly exposes the patient to the risk of under- or overexposure. In either situation (under or overexposure), the risk to the patient is not negligible. Under-exposure increases the risk of rejection and over-exposure increases the risk of adverse effects (nephrotoxicity, neurotoxicity, post-transplant diabetes, infections, etc.), hence the need for therapeutic pharmacological monitoring of this molecule. To date, the relationship between therapeutic efficacy and exposure indices is well established, but the relationship between adverse effects is still under debate. In this thesis, we focused on developing tools, using population pharmacokinetics and machine learning, to predict tacrolimus exposure but also to estimate renal function and exposure to an anti-infective drug used in transplant patients. We have also developed markers to follow longitudinal exposure in order to explore the influence of cumulative exposure and a fortiori that of cumulative overexposure to tacrolimus on the occurrence of adverse events, including the occurrence of post-transplant diabetes.Le tacrolimus, pierre angulaire de la thérapie immunosuppressive dans la transplantation d’organe solide, possède un intervalle thérapeutique étroit ainsi qu’une variabilité interindividuelle importante exposant rapidement le patient à un risque de sous- ou surexposition. Quelle que soit la situation (sous- ou surexposition), le risque encouru par le patient n’est pas négligeable. La sous-exposition augmente les risques de survenue d’un rejet et la surexposition celui d’apparition d’effets indésirables (néphrotoxicité, neurotoxicité, diabète post-transplantation, infections…), motivant la mise en place du suivi thérapeutique pharmacologique pour cette molécule. A ce jour, la relation entre l’efficacité thérapeutique et les indices d’exposition est bien établie cependant celle concernant les effets indésirables restent encore à débat. Dans ces travaux de thèse, nous nous sommes focalisés sur le développement d’outils, utilisant la pharmacocinétique de population et le machine learning, pour prédire l’exposition au tacrolimus mais également estimer la fonction rénale et l’exposition à un anti-infectieux, utilisé chez le transplanté. Nous avons aussi développé des marqueurs de suivi de l’exposition longitudinale afin d’explorer l’influence de l’exposition cumulée et a fortiori celle de la surexposition cumulée au tacrolimus sur la survenue d’effets indésirables notamment la survenue de diabète post-transplantation

Suivi du patient transplanté rénal traité par tacrolimus par pharmacocinétique de population et machine learning

Tacrolimus, the cornerstone of immunosuppressive therapy in solid organ transplantation, has a narrow therapeutic range and significant inter-individual variability that rapidly exposes the patient to the risk of under- or overexposure. In either situation (under or overexposure), the risk to the patient is not negligible. Under-exposure increases the risk of rejection and over-exposure increases the risk of adverse effects (nephrotoxicity, neurotoxicity, post-transplant diabetes, infections, etc.), hence the need for therapeutic pharmacological monitoring of this molecule. To date, the relationship between therapeutic efficacy and exposure indices is well established, but the relationship between adverse effects is still under debate. In this thesis, we focused on developing tools, using population pharmacokinetics and machine learning, to predict tacrolimus exposure but also to estimate renal function and exposure to an anti-infective drug used in transplant patients. We have also developed markers to follow longitudinal exposure in order to explore the influence of cumulative exposure and a fortiori that of cumulative overexposure to tacrolimus on the occurrence of adverse events, including the occurrence of post-transplant diabetes.Le tacrolimus, pierre angulaire de la thérapie immunosuppressive dans la transplantation d’organe solide, possède un intervalle thérapeutique étroit ainsi qu’une variabilité interindividuelle importante exposant rapidement le patient à un risque de sous- ou surexposition. Quelle que soit la situation (sous- ou surexposition), le risque encouru par le patient n’est pas négligeable. La sous-exposition augmente les risques de survenue d’un rejet et la surexposition celui d’apparition d’effets indésirables (néphrotoxicité, neurotoxicité, diabète post-transplantation, infections…), motivant la mise en place du suivi thérapeutique pharmacologique pour cette molécule. A ce jour, la relation entre l’efficacité thérapeutique et les indices d’exposition est bien établie cependant celle concernant les effets indésirables restent encore à débat. Dans ces travaux de thèse, nous nous sommes focalisés sur le développement d’outils, utilisant la pharmacocinétique de population et le machine learning, pour prédire l’exposition au tacrolimus mais également estimer la fonction rénale et l’exposition à un anti-infectieux, utilisé chez le transplanté. Nous avons aussi développé des marqueurs de suivi de l’exposition longitudinale afin d’explorer l’influence de l’exposition cumulée et a fortiori celle de la surexposition cumulée au tacrolimus sur la survenue d’effets indésirables notamment la survenue de diabète post-transplantation

Monitoring of renal transplant patients treated with tacrolimus using population pharmacokinetics and machine learning

Le tacrolimus, pierre angulaire de la thérapie immunosuppressive dans la transplantation d’organe solide, possède un intervalle thérapeutique étroit ainsi qu’une variabilité interindividuelle importante exposant rapidement le patient à un risque de sous- ou surexposition. Quelle que soit la situation (sous- ou surexposition), le risque encouru par le patient n’est pas négligeable. La sous-exposition augmente les risques de survenue d’un rejet et la surexposition celui d’apparition d’effets indésirables (néphrotoxicité, neurotoxicité, diabète post-transplantation, infections…), motivant la mise en place du suivi thérapeutique pharmacologique pour cette molécule. A ce jour, la relation entre l’efficacité thérapeutique et les indices d’exposition est bien établie cependant celle concernant les effets indésirables restent encore à débat. Dans ces travaux de thèse, nous nous sommes focalisés sur le développement d’outils, utilisant la pharmacocinétique de population et le machine learning, pour prédire l’exposition au tacrolimus mais également estimer la fonction rénale et l’exposition à un anti-infectieux, utilisé chez le transplanté. Nous avons aussi développé des marqueurs de suivi de l’exposition longitudinale afin d’explorer l’influence de l’exposition cumulée et a fortiori celle de la surexposition cumulée au tacrolimus sur la survenue d’effets indésirables notamment la survenue de diabète post-transplantation.Tacrolimus, the cornerstone of immunosuppressive therapy in solid organ transplantation, has a narrow therapeutic range and significant inter-individual variability that rapidly exposes the patient to the risk of under- or overexposure. In either situation (under or overexposure), the risk to the patient is not negligible. Under-exposure increases the risk of rejection and over-exposure increases the risk of adverse effects (nephrotoxicity, neurotoxicity, post-transplant diabetes, infections, etc.), hence the need for therapeutic pharmacological monitoring of this molecule. To date, the relationship between therapeutic efficacy and exposure indices is well established, but the relationship between adverse effects is still under debate. In this thesis, we focused on developing tools, using population pharmacokinetics and machine learning, to predict tacrolimus exposure but also to estimate renal function and exposure to an anti-infective drug used in transplant patients. We have also developed markers to follow longitudinal exposure in order to explore the influence of cumulative exposure and a fortiori that of cumulative overexposure to tacrolimus on the occurrence of adverse events, including the occurrence of post-transplant diabetes

Drug-induced cardiac toxicity and adverse drug reactions, a narrative review

International audienceDrug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity

Antipsychotic Abuse, Dependence, and Withdrawal in the Pediatric Population: A Real-World Disproportionality Analysis

Antipsychotic drugs (APs) aim to treat schizophrenia, bipolar mania, and behavioral symptoms. In child psychiatry, despite limited evidence regarding their efficacy and safety, APs are increasingly subject to off-label use. Studies investigating addictology-related symptoms in young people being scarce, we aimed to characterize the different patterns of AP misuse and withdrawal in children and adolescents relying on the WHO pharmacovigilance database (VigiBase®, Uppsala Monitoring Centre, Sweden). Using the standardized MedDRA Query ‘drug abuse, dependence and withdrawal’, disproportionality for each AP was assessed with the reporting odds ratio and the information component. A signal was detected when the lower end of the 95% confidence interval of the information component was positive. Results revealed mainly withdrawal symptoms in infants (under 2 years), intentional misuse in children (2 to 11 years), and abuse in adolescents (12 to 17 years). Olanzapine, risperidone, aripiprazole, and quetiapine were disproportionately reported in all age groups, with quetiapine being subject to a specific abuse signal in adolescents. Thus, in adolescents, the evocation of possible recreational consumption may lead to addiction-appropriate care. Further, in young patients with a history of AP treatment, a careful anamnesis may allow one to identify misuse and its role in the case of new-onset symptoms

The Neuropsychiatric Safety Profile of Lasmiditan: A Comparative Disproportionality Analysis with Triptans

International audienceMigraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT1B/1D receptor agonists, remain the first-line treatment, despite discouraged use in individuals at high cardiovascular risk. Lasmiditan, a selective lipophilic 5-HT1F agonist without vasoconstrictive effects, is an emerging option. We aimed to investigate the safety profile of lasmiditan in the WHO pharmacovigilance database (VigiBase®) using a comparative disproportionality analysis with triptans. VigiBase® was queried for all reports involving lasmiditan and triptans. Disproportionality analyses relied on the calculation of the information component (IC), for which 95% confidence interval (CI) lower bound positivity was required for signal detection. We obtained 826 reports involving lasmiditan. Overall, 10 adverse drug reaction classes were disproportionately reported with triptans, while only neurological (IC 1.6; 95% CI 1.5-1.7) and psychiatric (IC 1.5; 95% CI 1.3-1.7) disorders were disproportionately reported with lasmiditan. Sedation, serotonin syndrome, euphoric mood, and autoscopy had the strongest signals. When compared with triptans, 19 out of 22 neuropsychiatric signals persisted. The results of our analysis provide a more precise semiology of the neuropsychiatric effects of lasmiditan, with symptoms such as autoscopy and panic attacks. The cardiovascular adverse drug reaction risk with triptans was confirmed. In contrast, caution is warranted with lasmiditan use in patients with neurological or psychiatric comorbidities or serotonin syndrome risk. Our study was hindered by pharmacovigilance flaws, and further studies should help in validating these results. Our findings suggest that lasmiditan is a safe alternative for migraine treatment, especially when the neuropsychiatric risk is outweighed by the cardiovascular burden

A Hybrid Algorithm Combining Population Pharmacokinetic and Machine Learning for Isavuconazole Exposure Prediction

International audienceObjectives Maximum a posteriori Bayesian estimation (MAP-BE) based on a limited sampling strategy and a population pharmacokinetic (POPPK) model is used to estimate individual pharmacokinetic parameters. Recently, we proposed a methodology that combined population pharmacokinetic and machine learning (ML) to decrease the bias and imprecision in individual iohexol clearance prediction. The aim of this study was to confirm the previous results by developing a hybrid algorithm combining POPPK, MAP-BE and ML that accurately predicts isavuconazole clearance. Methods A total of 1727 isavuconazole rich PK profiles were simulated using a POPPK model from the literature, and MAP-BE was used to estimate the clearance based on: (i) the full PK profiles (refCL); and (ii) C24h only (C24h-CL). Xgboost was trained to correct the error between refCL and C24h-CL in the training dataset (75%). C24h-CL as well as ML-corrected C24h-CL were evaluated in a testing dataset (25%) and then in a set of PK profiles simulated using another published POPPK model. Results A strong decrease in mean predictive error (MPE%), imprecision (RMSE%) and the number of profiles outside ± 20% MPE% (n-out20%) was observed with the hybrid algorithm (decreased in MPE% by 95.8% and 85.6%; RMSE% by 69.5% and 69.0%; n-out20% by 97.4% and 100% in the training and testing sets, respectively. In the external validation set, the hybrid algorithm decreased MPE% by 96%, RMSE% by 68% and n-out20% by 100%. Conclusion The hybrid model proposed significantly improved isavuconazole AUC estimation over MAP-BE based on the sole C24h and may improve dose adjustment