Christian Funck-Brentano

Sorbonne Université (Emeritus Professor) · Department of Pharmacology

Background Drug-induced QT interval prolongation raises the risk of fatal arrhythmia and is a central issue in safety pharmacology. Yet individual QT drug response is highly variable, and risk stratification remains a challenge. We hypothesized that genetic factors underlying the baseline QT influence this variation in QT drug response. Methods A...

Therapeutic drug monitoring (TDM) involves measuring and interpreting drug concentrations in biological fluids to adjust drug dosages. In onco‐hematology, TDM guidelines for oral molecular targeted therapies (oMTTs) are varied. This study evaluates a quantitative approach with a score to predict the clinical usefulness of TDM for oMTTs. We identifi...

Background: Drug-induced QT interval prolongation raises the risk of fatal arrhythmia and is a central issue in safety pharmacology. Yet individual QT drug response is highly variable, and risk stratification remains a challenge. We hypothesized that genetic factors underlying the baseline QT influence this variation in QT drug response. Methods: A...

3091 Background: Therapeutic drug monitoring (TDM) consists in measuring and interpreting drug concentrations in biological fluids to personalize drug dosage. This method is widely used for drugs with a narrow therapeutic index ( e.g., immunosuppressants or neuroleptics agents). In onco-hematology, current recommendations of TDM for oral molecularl...

Background: Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intrave...

Background Consumption of herbs, food used as medicine and dietary supplements (HFDSs) is common in cancer patients. Herbs and food-drug interactions (HFDIs) can lead to serious adverse effects and can be prevented. We previously reviewed cytochrome P-450 (CYP)-mediated HFDI for 261 HFDSs and we classified the risk of CYP inhibition and induction o...

Changes in the cardio-metabolomics profile and hormonal status have been associated with long QT syndrome, sudden cardiac death and increased mortality. The mechanisms underlying QTc duration are not fully understood. Therefore, an identification of novel markers that complement the diagnosis in these patients is needed. In the present study, we pe...

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 20...

The extent of sotalol‐induced QTc prolongation on the electrocardiogram, is variable among subjects and influenced by sex. However, the influence of baseline QTc on the extent of drug‐induced QTc prolongation remains unclear. This was studied around peak plasma concentration in a large cohort of 376 healthy male and 614 healthy female subjects who...

The prevalence and incidence of cardiac pro-arrhythmic disorders are often influenced by sex due to specific effects on the QT interval. Androgens shorten QT, which may be protective against acquired long QT syndromes and their related arrhythmias in men such as torsade de pointes (TdP). On the other hand, androgens can potentiate Brugada and early...

Aims Congenital long-QT syndromes (cLQTS) or drug-induced long-QT syndromes (diLQTS) can cause torsade de pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy for the identification of drugs at the high risk of TdP relies on measuring the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG). However, Q...

To the Editor Marcusa et al¹ have examined the influence of baseline low-density lipoprotein cholesterol (LDL-C) levels on percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition. Using this mode of calculation, they report a higher percentage reduction in LDL-C with evolocumab in patients with lower baseline LDL-C levels, compared...

The prevalence and incidence of cardiac pro-arrhythmic disorders are often influenced by sex due to specific effects on the QT interval. Androgens shorten QT, which may be protective against acquired long QT syndromes and their related arrhythmias in men such as torsade de pointes (TdP). On the other hand, androgens can potentiate Brugada and early...

Aims With the explosion of anticancer drugs, an emerging concern is the risk for drug-induced sudden death (SD) via ventricular arrhythmias (VA). Methods and results We used the international pharmacovigilance database VigiBase (n = 18 441 659 reports) to compare drug-induced long QT (diLQT, n = 18 123) and VA (n = 29 193) including torsade de poi...

Background: Ciprofloxacin is an antibiotic used in osteoarticular infections owing to its very good bone penetration. Very few pharmacokinetic data are available in this population. Objectives: To investigate oral ciprofloxacin population pharmacokinetics in adult patients treated for osteoarticular infections and propose guidance for more effec...

Objectives: Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefideroco...

Background: Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. Methods: We analysed PCD/T in patients treated with D+T for metastatic melanoma. We col...

Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products,...

Background: Hydroxychloroquine (HCQ) is an antimalarial agent given to patients with systemic lupus erythematosus (SLE) as first-line therapy. It alleviates childhood-onset systemic lupus erythematosus cSLE skin and musculoskeletal disease, decreasing disease activity and flares. HCQ concentration-effect relationships in children remains unknown....

Résumé Introduction Les patients ayant un cancer solide ou hématologique ont été considérés comme étant plus susceptibles de contracter une infection à SARS-COV-2, et de développer plus fréquemment des complications graves. Nous avons voulu comparer les caractéristiques cliniques et le pronostic des patients atteints de COVID-19 avec ou sans cance...

Congenital or drug-induced long-QT syndromes can cause Torsade-de-Pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy to identify individuals at high risk of TdP consists on measuring the QT duration on the electrocardiogram (ECG), shown to provide limited information. We propose an original method, including training dee...

Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and developmen...

Kinase inhibitors (KIs) and antiandrogen drugs (AAs) are oral anticancer drugs with narrow therapeutic index that exhibit high inter- and intra-individual variability. We describe here a UPLC-MS/MS method for the simultaneous quantification of nine KIs: cobimetinib, dasatinib, ibrutinib, imatinib, nilotinib, palbociclib, ruxolitinib, sorafenib and...

Background: Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. Methods: We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 sampl...

For millennia, medicine was empirical and dominated by beliefs, dogmas and sorcery. Evidence-based medicine then emerged over the last two centuries as a major source of progress towards enlightened clinical practice. Yet, the design of randomized clinical trials and observational studies and, even more so, their methods of data collection and anal...

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May...

Background: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. Methods: Lower limb arterial calcification scores wer...

Background It is unclear whether HIV infection affects the long‐term prognosis after an acute coronary syndrome (ACS). The objective of the current study was to compare rates of major adverse cardiac and cerebrovascular events after a first ACS between people living with HIV (PLHIV) and HIV‐uninfected (HIV−) patients, and to identify determinants o...

Although hydroxychloroquine and azithromycin, alone or in combination, have been proposed for treatment of patients with coronavirus disease 2019 (COVID-19),1 their potential cardiovascular toxicities had limited consideration in this new clinical environment. We aimed to determine whether these drugs were associated with an increased reporting of...

A recent Lancet Article by Mandeep Mehra and colleagues, which reported adverse events associated with hydroxychloroquine or chloroquine treatment in patients with COVID-19, has been retracted by three of the authors,1 along with our linked Comment that provided a commentary on the Article and its findings,2 because the veracity of the data underly...

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to impaired cortisol biosynthesis. Treatment includes glucocorticoid supplementation. We studied the specific metabolomics signatures in CAH patients using two different algorithms. Methods: In a case-control study of CAH patients matched on sex and age with...

Background: While hydroxychloroquine and azithromycin, alone or in combination, have been proposed for treatment of Covid-19 patients, their potential cardiovascular adverse-drug-reactions (CV-ADRs) have been scarcely reported. Methods: We used VigiBase, the international pharmacovigilance database thru 03/01/2020, to perform a disproportionality s...

Background: Lower limb arterial calcification is a frequent, underestimated but serious diabetic complication. The DIACART study is a prospective cohort study designed to evaluate the determinants of lower limb arterial calcification progression in 198 patients with Type 2 Diabetes. Methods: Lower limb arterial calcification score was determined by...

Background: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes. Methods: Lower limb arterial calcification scores were d...

[This corrects the article DOI: 10.1371/journal.pone.0229145.].

Aims: The explosion of novel anticancer therapies has meant emergence of cardiotoxicity signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer drugs in inducing AF are scarce. Using the World Health Organization individual case safety report database, VigiBase®, we aimed to determine the association betwee...

Aims We investigated the effect of gadopiclenol, a new gadolinium‐based contrast agent, on the QTc interval at clinical and supraclinical dose, considering the relative hyperosmolarity of this product. Methods This was a single centre, randomized, double‐blind, placebo‐ and positive‐controlled, 4‐way crossover study. Forty‐eight healthy male and f...

A recent editorial in this journal elegantly discussed the influence of cardiovascular diseases on COVID-19 [1]. Another issue is associated with the potential risk of cardiac arrhythmias with chloroquine or hydroxychloroquine (sometimes combined with azithromycin), which are being proposed to treat COVID-19. All three drugs individually can rarely...

Aims/Hypothesis Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated...

We thank Chen et al. for their comments on our recently published study showing that androgen-deprivation therapies (ADT) can induce QT prolongation and Torsade de pointes (TdP). In the manuscript, we identified a clinical signal using the VigiBase pharmacovigilance database and then provided biological plausibility for our observations by performi...

Background: Fluoroquinolones and rifampicin are antibiotics frequently used for the treatment of osteoarticular infections, and their therapeutic drug monitoring is recommended. The aim of this study was to develop and validate a rapid and selective method of simultaneous quantification of levofloxacin, ciprofloxacin, moxifloxacin and rifampicin w...

Over the past decades, assessment of drug safety and of their benefits harms balance has been profoundly modified by the availability of large databases and computerized automated statistical approaches. Improvement of digital data storage capacity has been applied to pharmacovigilance reports. VigiBase, the international pharmacovigilance database...

Background: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. Methods: We searc...

Aims: Following the serious adverse events that occurred in January 2016 during the BIA 10-2474 First-in-Human study, the French Ministry of Health asked the Regional Health Agencies to inspect operations at all research sites conducting phase I/II clinical trials of experimental drugs. The aim of this study was to assess the medical relevance of...

Background Mineralocorticoid receptor antagonists ( MRA s) have emerged as potential atrial fibrillation ( AF ) preventive therapy, but inconsistent results have been reported. We aimed to examine the effects of MRA s on AF occurrence and explore factors that could influence the magnitude of the effect size. Methods and Results PubMed, Embase, and...

Background: Abiraterone and enzalutamide are recently-approved androgen deprivation therapies (ADTs) for metastatic prostate cancer, with unknown cardiac safety profiles. Abiraterone has a propensity to hypermineralocorticism on top of androgen deprivation, so might carry an additional risk for atrial tachyarrhythmia (AT) and heart failure (HF) co...

Aim Male hypogonadism, arising from various etiologies including androgen-deprivation therapies (ADT), has been reported as a risk-factor for acquired long-QT (aLQT) and Torsades de pointe (TdP). A full description of clinical features of aLQTS associated with ADT and of underlying mechanisms are lacking. Method and results We searched the WHO pha...

Background Abiraterone and enzalutamide are recently approved androgen deprivation therapies (ADT) for metastatic prostate cancer. The cardiac safety profile for the two drugs is unknown. Methods Using French and World Health Organization (WHO) pharmacovigilance databases, we performed a disproportionality-analysis of suspected adverse-drug-reacti...

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We sear...

Background. HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represe...

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searc...

BACKGROUND: Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clini...

Aims Drug‐induced aseptic meningitis (DIAM) is an adverse drug reaction of exclusion; only few studies have addressed this iatrogenic disease. The aim was to characterize DIAM and to identify suspected drugs. Methods Data were collected from the analysis of the French Pharmacovigilance Database from inception (1 January 1985) to 8 March 2017. All...

Background. Patients at increased cardiovascular (CV) risk, noticeably hypertensive patients, have multiple CV risk factors which may be treatment targets. LDLcholesterol is one of such targets. Using the SPRINT cohort, studying the cardiovascular outcomes of hypertensive patients at increased CV risk, this post-hoc study aimed to assess the associ...

Protein kinase inhibitors (PKI) are a growing class of anticancer agents. They are prescribed with flat doses, and their oral administration is associated with interindividual variability in exposure. Patients can be over- or underexposed, due to numerous factors. We reviewed key pharmacokinetic concepts and mechanisms by which PKIs prescription co...

Background: Rivaroxaban is a direct factor Xa inhibitor with substantial inter-individual pharmacokinetic (PK) variability. Pharmacodynamic (PD) variability, especially assessed with thrombin generation (TG), has been less documented. Objectives: i/to assess TG parameter time-profiles in healthy volunteers, TG being studied under different condi...

The first administrations of a molecule to humans, so-called phase I studies of drug development, follow experimental animal studies which allow to have a first assessment of the pharmacological effects and toxicity of the molecule under development. Typically, these studies are performed in "healthy" subjects or in relapsing patients with cancer....

Objectives: P-glycoprotein (P-gp), the product of the ABCB1 gene, is involved in the transport of aldosterone and cortisol in adrenal cells in vitro but its physiological role in humans remains controversial. Our objective was to test the influence of P-gp polymorphisms on aldosterone. Methods: We evaluated plasma aldosterone concentration (PAC),...

9541 Background: Dabrafenib (D) and trametinib (T) are highly ative in BRAF V600mut melanoma pts. One previous study suggested high PCD to be associated with adverse effects (AE) but not with tumor response. We investigated the relationship between PCD/T and tumor control or AE. Methods: PCD/T were evaluated with high-performance liquid chromatogra...

Background: Medial calcification in diabetes contributes to the arterial occlusive process occurring below the knee level. Adiponectin is an adipokine with atheroprotective properties and possible protective role against arterial calcification. The aim of the study was to investigate, in type 2 diabetes, the link between vascular expression and se...

Breast and prostate cancers are among the most prevalent cancers worldwide. Oestradiol and progesterone are major drivers for breast cancer proliferation, and androgens for prostate cancer. Endocrine therapies are drugs that interfere with hormone-activated pathways to slow cancer progression. Multiple new breakthrough drugs improving overall survi...

Inhibitors of mechanistic target of rapamycin (mTOR inhibitors) are used as antiproliferative immunosuppressive drugs and have many clinical applications in various drug combinations. Experience in transplantation studies has been gained regarding the side effect profile of these drugs and the potential benefits and limitations compared with other...

Background: Hydroxychloroquine (HCQ) is approved for the treatment of systemic lupus erythematosus (SLE). Therapeutic drug monitoring (TDM) of HCQ is necessary to detect non-adherence and to improve treatment efficacy in SLE patients. Liquid chromatographic-tandem mass spectroscopy and HPLC-fluorescent methods are currently used to measure whole b...

Several antimalarial drugs are known to prolong ventricular repolarization as evidenced by QT/QTc interval prolongation. This can lead to Torsades de Pointes, a potentially lethal ventricular arrhythmia. Whether this is the case with artemisinin-based combination therapies (ACTs) remains uncertain. Assessment of the extent of QTc prolongation with...

QT/QTc interval prolongation reflects delayed cardiac repolarization which can lead to Torsade de Pointes and sudden death. Many antimalarial drugs prolong QT/QTc interval. However, due to confounding factors in patients with malaria, the precise extent of this effect has been found to be highly variable among studies. We compared the effects of di...

Introduction L’association D + T est un traitement majeur des mélanomes avancés mutés BRAFV600 avec un risque d’échappement et d’EI. Nous avons recherché un lien entre concentrations plasmatiques de D et T (CPD/T) avec la réponse tumorale et les EI. Matériel et méthodes Dosages prospectifs des CPD/T (par HPCL et spectrométrie de masse) chez des pa...

Hypogonadism as a Reversible Cause of Torsades de Pointes in Men. Salem JE, Waintraub X, Courtillot C, Shaffer CM, Gandjbakhch E, Maupain C, Moslehi JJ, Badilini F, Haroche J, Gougis P, Fressart V, Glazer AM, Hidden-Lucet F, Touraine P, Lebrun-Vignes B, Roden DM, Bachelot A, Funck-Brentano C. Circulation. 2018 Jul 3;138(1):110-113. doi: 10.1161/C...

Abstract OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. METHODS: We performed a disproportionality analysis using...

Clinical practice guidelines summarize and evaluate all available evidence at the time of the writing process on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome as well as the risk–benefit ratio of particul...

These Guidelines represent the third time that the ESC and EACTS have brought together cardiologists and cardiac surgeons in a joint Task Force to review the ever-increasing body of evidence, with the mission of drafting balanced, patient-centred practice Guidelines on myocardial revascularization. Summaries of the key changes in comparison with th...

Importance Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are bioma...

Long QT intervals corrected for rate (QTc) >480 to 500 milliseconds predispose to the polymorphic ventricular tachycardia torsades de pointes (TdP).1 Because QTc is shorter and TdP is less frequent in men than in women and because testosterone shortens ventricular repolarization, we examined the effect of hypogonadism and androgen deprivation thera...

Objective: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. Methods: We performed a disproportionality analysis using the Eur...

Significant advances in cancer treatment have resulted in decreased cancer related mortality for many malignancies with some cancer types now considered chronic diseases. Despite these improvements, there is increasing recognition that many cancer patients or cancer survivors can develop cardiovascular diseases, either due to the cancer itself or a...

Posaconazole is a triazole antifungal used to prevent invasive fungal infections (IFIs) in patients receiving chemotherapy or haemotopoietic stem cell transplantation. Due to highly variable bioavailability of the oral suspension formulation, a delayed-release tablet was developed which showed improved bioavailability. A minimal target posaconazole...

Complex influence of endocrine and neuro-vegetative disorders on ventricular repolarization in diabetic patients. • Background Diabetic patients have an increased QT interval duration corrected for heart rate (QTcF) and an increased risk of sudden death, as compared to healthy subjects. Diabetics are characterized by increased insulin resistance...

The ratio of early diastolic trans-mitral flow velocity to tissue-Doppler mitral annular early diastolic velocity (E/e'), and left ventricular end-diastolic pressure(LVEDP) have been shown to be correlated at rest, provided that patients are not on positive inotropic drugs. Data concerning the latter correlation during exercise stress are conflicti...

Background Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones...