Nicolas Picard- PharmD, PhD
- Professor at University of Limoges
Nicolas Picard
- PharmD, PhD
- Professor at University of Limoges
About
174
Publications
17,161
Reads
How we measure 'reads'
A 'read' is counted each time someone views a publication summary (such as the title, abstract, and list of authors), clicks on a figure, or views or downloads the full-text. Learn more
3,861
Citations
Introduction
Current institution
Publications
Publications (174)
Mavacamten, the first drug in the class of β‐cardiac myosin modulator, is used for the treatment of patients with hypertrophic cardiomyopathy. This orally administered drug demonstrates wide interpatient variability in pharmacokinetics parameters, due in part to variant CYP2C19 alleles. Individuals who are CYP2C19 poor metabolizers have increased e...
Transplantation is the treatment of choice for several end-stage organ defects: it considerably improves patient survival and quality of life. However, post-transplant recipients may experience episodes of rejection that can favor or ultimately lead to graft loss. Graft maintenance requires a complex and life-long immunosuppressive treatment. Diffe...
Post-transplant diabetes mellitus (PTDM) is one of the most common and deleterious comorbidities after solid organ transplantation (SOT). Its incidence varies depending on the organs transplanted and can affect up to 40% of patients. Current research indicates that PTDM shares several common features with type 2 diabetes mellitus (T2DM) in non-tran...
Les médicaments produisent des effets variables selon les individus. De nombreux facteurs, physiologiques, pathologiques, environnementaux et génétiques, sont impliqués. La pharmacogénétique est la discipline qui vise à identifier les facteurs génétiques de variabilité de réponse médicamenteuse. Des tests peuvent revêtir un caractère obligatoire, n...
L’implémentation de tests non rédactionnels entraîne de nouveaux usages dans l’évaluation des connaissances des étudiants. Cette recherche s’intéresse à l’évolution des tests non-rédactionnels et à l’impact du niveau de maitrise des enseignants sur Moodle dans le choix du format et du niveau de complexité des questions. Il ressort de notre étude qu...
Regarding animal experiments in pharmacology teaching, ethical considerations led us to examine an alternative approach to the use of living animals. This study aimed to assess whether digital tools could replace live animal experiments in terms of motivation and knowledge acquisition. The study was carried out with students enrolled in the 5th yea...
Background and Purpose
Opioids and benzodiazepines are frequently combined in medical as well as in non‐medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and dicla...
When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is...
Background
Tacrolimus has a narrow therapeutic range and requires dose adjustment, usually based on the trough blood concentration but preferably on the area under the concentration–time curve over 12 h post-dose (AUC0–12h). The single-arm, multicentre, clinical study IMPAKT aimed: (i) to develop, in de novo kidney transplant recipients, pharmacoki...
Genetic variations in CYP3A4, CYP3A5, and m-TOR could contribute to interpatient variability regarding m-TOR inhibitors pharmacokinetics or cellular effects. The purpose of this study was to evaluate the influence of selected candidate variations in these genes on everolimus pharmacokinetics, efficacy, and toxicity in cancer patients. Thirty-four p...
• Mycophenolic acid (MPA) has become a cornerstone of immunosuppressive therapy, in particular for transplant patients. In the gastrointestinal tract, the liver and the kidney, MPA is mainly metabolized into phenyl-β-D glucuronide (MPAG). Knowledge about the interactions between MPA/MPAG and membrane transporters is still fragmented.
• The aim of t...
Résumé
Tout récemment, la société savante internationale de pharmacologie-toxicologie biologique a émis des recommandations sur le suivi thérapeutique pharmacologique (STP) du tacrolimus. Cette conférence de consensus fait suite à la première du genre, laquelle avait été publiée en 2009. Dans ce document, la place du STP du tacrolimus pour les quat...
Background:
Plasma concentrations of fluoropyrimidine exhibit a wide inter-individual variability that depends mainly on the activity of dihydropyrimidine dehydrogenase (DPD), its major catabolic enzyme. Patients with low DPD activity are at increased risk of overexposure and often severe, sometimes lethal toxicity. This study aimed to develop a q...
Pharmacogenetics, which concepts are known for a long time, is entering a new period at least as far as its practical applications for patients are concerned. In recent years there have been more and more initiatives to promote widespread dissemination, and health authorities are increasingly incorporating these concepts into drug labels. In France...
The efficiency of new generation sequencing methods and the reduction of their cost has led pharmacogenomics to gradually supplant pharmacogenetics, leading to new applications in personalized medicine along with new perspectives in drug design or identification of drug response factors. The amount of data generated in genomics fits the definition...
Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus...
Conventional therapeutic drug monitoring refers to the individualization of drug dosage by maintaining plasma or blood drug concentrations within a targeted therapeutic range. Accordingly, an individualized dose is proposed to the clinician according to the drug plasma or blood concentration using an a posteriori approach. Pharmacogenetics (PGx) ha...
A 67‐year‐old man was admitted to the emergency department about 5 h after deliberate self‐poisoning with 300 mg of Apixaban. The clinical examination did not show any organ dysfunctions or haemorrhagic signs, and the patient's life was not in danger. The first analysis, upon admission, showed a concentration of 2655 μg l⁻¹ of Apixaban. The Cmax wa...
Résumé
Le parcours de soins d’un patient cancéreux, du diagnostic au retour à domicile, est complexe et a fait l’objet de nombreuses mesures d’amélioration et de réglementation pour assurer une qualité optimale de prise en charge. Il est aujourd’hui pluridisciplinaire et rythmé par une succession d’étapes qui doivent être connues du pharmacien d’of...
Résumé
La polykystose rénale autosomique dominante est une maladie génétique caractérisée par le développement de kystes entraînant, à terme, une insuffisance rénale. Le tolvaptan est le premier médicament indiqué pour ralentir sa progression. Il nécessite de la part du pharmacien des conseils éclairés pour sécuriser au mieux le traitement du patie...
Purpose:
Chemotherapy dosing in neonates represents a major clinical challenge because of a lack of clinical pharmacology information in this patient population. In this study, we investigate the use of cisplatin dose adaptation based on therapeutic drug monitoring in a 2-week-old neonate with localized hepatoblastoma.
Methods:
Cisplatin concent...
This work investigated, in two large cohorts of French renal transplants treated with tacrolimus, the influence of donor and recipient ABCB1, CYP3A4 and CYP3A5 genotypes on the risk of allograft loss. A discovery and a replication population of 330 and 369 adult renal transplant patients, each from a different transplantation centre and all receivi...
The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity...
Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0.8% of patients, resulting in a real public health problem. The main origin of FU-related toxicities is a deficiency of dihydropyrimidine de...
Background:
Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between v...
Résumé
Le suivi thérapeutique pharmacologique consiste à mesurer la concentration sanguine d’un médicament afin de déterminer si une adaptation de posologie est nécessaire pour optimiser l’efficacité thérapeutique tout en minimisant le risque d’effets indésirables. Le pharmacien d’officine peut être amené à répondre aux interrogations des préleveur...
Designer benzodiazepines (DBZDs) have become of particular importance in the past few years. The metabolite monitoring of DBZD in biological fluids could be of great interest in clinical and forensic toxicology. However, DBZD metabolites are not known or not commercially available. The identification of some DBZD metabolites has been mostly explore...
Objectif
L’infection par cytomégalovirus (CMV) est redoutée chez le patient transplanté sous traitement immunosuppresseur. Le ganciclovir (GCV) est la molécule la plus utilisée en prophylaxie ou pour le traitement de ces infections, mais présente une toxicité hématologique conduisant à la diminution des doses ou à l’arrêt du traitement, favorisant...
Introduction:
Therapeutic drug monitoring (TDM) of everolimus is not performed in oncology and no trough level (C0) target has been yet defined. The aim of this study was to determine everolimus C0 target for toxicity and efficacy.
Materials and methods:
Clinical, biological and radiologic data from 54 patients were collected. Toxicity event was...
Therapeutic drug monitoring is already widely used for immunosuppressive drugs due to their narrow therapeutic index. This article summarizes evidence reported in the literature regarding the pharmacogenetics of i) immunosuppressive drugs used in transplantation and ii) azathioprine used in chronic inflammatory bowel disease. The conditions of use...
More than 50 laboratories offer pharmacogenetic testing in France. These tests are restricted to a limited number of indications: prevention of serious adverse drug reactions; choice of most appropriate therapeutic option; dose adjustment for a specific drug. A very small proportion of these tests are mentioned in drug information labeling and the...
Plus de 50 laboratoires de biologie médicale ont développé une activité spécialisée de pharmacogénétique en France. Le recours à ces tests demeure encore restreint à un nombre limité d’indications visant à prévenir un risque d’effet indésirable médicamenteux grave, décider de la prise en charge thérapeutique la plus adaptée ou encore ajuster la pos...
Résumé
L’individualisation thérapeutique est déjà largement utilisée pour les immunosuppresseurs du fait de leur faible index thérapeutique. Cet article fait la synthèse des éléments scientifiques disponibles pour la pharmacogénétique : (i) des médicaments immunosuppresseurs utilisés en transplantation et (ii) de l’azathioprine dont la principale i...
Background:
This study investigated the influence of the CYP3A4*22, CYP3A5*3, and ABCB1 exons 12, 21, and 26 polymorphisms in donors and recipients on clinical outcomes and renal function in 170 liver transplant patients on cyclosporin A (CsA) or tacrolimus (Tac).
Methods:
Allelic discrimination assays were used for genotyping. Multivariate time...
Background:
Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1....
Ganciclovir (GCV) is the cornerstone of cytomegalovirus prevention in transplant patients. It is associated with problematic adverse hematological effects in this population of immunosuppressed patients, which may lead to dose reduction thus favoring resistance. GCV crosses the membranes of cells, is activated by phosphorylation, and then stops the...
Objectifs
Déterminer si un surdosage en oxycodone pourrait être favorisé par la prise concomitante d’une benzodiazépine de synthèse (BZS), le diclazépam.
Méthodes
Dans ce contexte, nous avons étudié in vitro les voies métaboliques du diclazépam, puis l’influence du diclazépam sur le métabolisme de l’oxycodone. (i) Étude du métabolisme du diclazépa...
Objectif
Les benzodiazépines de synthèse (BZS) font partie des produits de synthèse disponibles sur Internet à des prix très attractifs. La prise concomitante des BZS avec d’autres produits d’abus est un phénomène croissant. Cette étude visait à explorer, in vitro, le métabolisme des BZS les plus consommées en Europe [1] : diclazépam, étizolam, des...
With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with...
In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of t...
Résumé
L’officine est équipée de logiciels permettant de détecter les interactions médicamenteuses sur les ordonnances, ce qui facilite grandement la tâche. Toutefois, lors d’une première lecture, il est nécessaire de se renseigner sur le profil du patient et les risques encourus. Pour cela, il convient de suivre une démarche précise et standardisé...
Résumé
Les interactions pharmacocinétiques sont nombreuses et variées. Elles se produisent lorsqu’un médicament entraîne des modifications de concentration d’un autre médicament pris simultanément, autrement dit lorsqu’il modifie sa pharmacocinétique.
Résumé
Les interactions médicamenteuses de nature pharmacodynamique sont caractérisées par des additions d’effets notamment sédatifs, hypotenseurs, hypokaliémiants ou des antagonismes pharmacologiques, par exemple lorsqu’un médicament dopaminergique est associé à un neuroleptique à propriété anti-dopaminergique.
Résumé
Les torsades de pointe peuvent être induites par certaines affections médicales et congénitales, mais elles sont le plus souvent provoquées par des interactions médicamenteuses. Ce problème cardiaque consiste en un accès de tachycardie ventriculaire avec modification à l’électrocardiogramme, pendant lequel le débit circulatoire n’est plus as...
Aim:
To investigate the potential influence of variants in genes involved in the calcineurin pathway on the efficacy and toxicity of calcineurin inhibitors in renal transplantation.
Materials & methods:
Twenty-three polymorphisms in thirteen genes were tested in 381 renal transplant recipients receiving ciclosporin (n = 221) or tacrolimus (n = 1...
Interindividual variability in immunosuppressive drug responses might be partly explained by genetic variants in proteins involved in the immune response or associated with IS pharmacodynamics. On a general basis, the pharmacogenetics of drug target proteins is less known and understood than that of proteins involved in drug disposition pathways. T...
To investigate the impact of epoetin beta (EPO) on sustained virological response (SVR) in hepatitis C virus (HCV)-infected patients treated with peginterferon–ribavirin (RBV). Controlled, randomized, pragmatic multicenter study to assess 2 strategies, ie, the use (EPO group) or nonuse (control group) of EPO in terms of achieving SVR in treatment-n...
Objectives:
Ganciclovir is the most widely used treatment for cytomegalovirus infections. However, neutropenia is a frequent associated adverse effect leading to a decrease in the ganciclovir dose or discontinuation of the therapy, thereby favouring viral resistance. In the present study, the objectives were: (i) to describe the pharmacokinetics o...
In association with therapeutic drug monitoring (TDM) of immunosuppressive drugs, pharmacogenetics has rapidly emerged as an additional tool to refine dose selection or, more interestingly to select, a priori, the first dose to administer. Pharmacogenetic biomarkers are now readily available in most transplantation centers, at a limited cost and wi...
In response to the urgent need for new, reliable biomarkers to complement the guidance of the immunosuppressive therapy a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical...
We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia.
Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity and relapse were inv...
The modulation of the immune system following solid organ transplantation has made considerable progress with new immunosuppressive regimens and has considerably improved rejections rates. The improvement in long-term allograft survival is, however, modest. A complex network of cytokines, chemokines, adhesion, activation and co-stimulatory molecule...
Epigenetic research in pharmacolog
Objectives: Ganciclovir is the most widely used treatment for cytomegalovirus infections. However, neutropenia is a frequent associated adverse effect leading to a decrease in the ganciclovir dose or discontinuation of the therapy, thereby favouring viral resistance. In the present study, the objectives were: (i) to describe the pharma-cokinetics o...
Irinotecan is a major drug in the treatment of advanced colorectal cancer. Its active form is the SN38 metabolite, which is cleared by the biliary route after glucuronidation by uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1). UGT1A1 activity exhibits a wide inter-subject variability, in part related to UGT1A1 gene polymorphisms. The prese...
Ganciclovir (GCV) is prescribed for cytomegalovirus infection which is a major issue in immunodepressed patients. It is however characterized by hematological toxicity. A better understanding of GCV concentration-effects relationships implies the measurement of intracellular forms. The objective of this study was to develop a method to measure GCV...
Résumé
L’irinotécan est un agent cytotoxique largement utilisé dans le traitement des cancers colorectaux avancés. Son activité anticancéreuse dépend de sa bioactivation en métabolite SN38 et son élimination se fait sous forme glucuronoconjuguée par l’enzyme hépatique uridine diphosphate glucuronosyltransférase 1A1 (UGT1A1). Il existe des variation...
Different associations between single nucleotide polymorphisms (SNPs) in cellular target, metabolism enzymes or transport proteins, and biopsy-proven acute rejection (BPAR) or adverse events have been reported in transplant patients receiving mycophenolate mofetil. This work aimed to study these in patients on enteric-coated mycophenolate sodium (E...
We investigated the associations between variants in genes coding for enzymes and transporters related to the 6-mercaptopurine pathway and clinical outcomes in pediatric patients with acute lymphoblastic leukemia. Materials & methods: Statistical association between gender, age and genotypes of selected SNPs, and the risks of hematological toxicity...
: This case report is about a suspected interaction between argatroban, a direct thrombin inhibitor, and cyclosporine, which occurred in a 60-year-old patient after a second heart transplantation. We explored 4 possible mechanisms of interaction, which are an analytical interference, an idiopathic hemodilution, an increase of renal and hepatic clea...
Background:
Recent studies have identified new candidate polymorphisms in the genes related to CYP3A activity or calcineurin inhibitor dose requirements in kidney transplant recipients. These genes and polymorphisms are CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (rs35599367-C>T; *22); POR [P450 (cytochrome) oxidoreductase] (rs1...
This work rationalizes the glucuronidation process (one of the reactions of the phase II metabolism) for drugs having a carboxylic acid moiety. At this stage, acylglucuronides (AG) metabolites are produced, that have largely been reported in the literature for various drugs (e.g., mycophenolic acid (MPA), diclofenac, ibuprofen, phenylacetic acids)....
Background: Ethylglucuronide (EtG) determination is increasingly used in clinical and forensic toxicology to document ethanol consumption. The enzymes involved in EtG production, as well as potential interactions with common drugs of abuse, have not been extensively studied. Methods: Activities of human liver (HLM), kidney (HKM) and intestinal (HIM...
The mammalian target of rapamycin (m-TOR) inhibitor sirolimus is an immunosuppressive drug used in kidney transplantation. m-TOR binds with Raptor and phosphorylates p70S6 kinase, a protein involved in numerous cell signalling pathways. We examined the association of candidate polymorphisms in m-TOR, Raptor and p70S6K, sirolimus dose and exposure,...
This article describes the development of a procedure for the simultaneous evaluation of the activity of six different uridine diphosphate (UDP)-glucuronyltransferases (UGTs) in human liver microsomes (HLMs). The method consists of incubations of probe substrates for UGT1A1 (etoposide), UGT1A3 (chenodeoxycholic acid), UGT1A4 (trifluoperazine), UGT1...
Immunosuppressants have narrow therapeutic ranges and have been rapidly identified as good candidates for pharmacogenomic research. In most cases, in vitro studies supported the hypothesis that polymorphisms in genes involved in disposition pathways (metabolic enzymes, or influx or efflux transporters) could affect their dose-concentration relation...
The mTOR inhibitors (ImTORs) sirolimus (SRL) and everolimus (EVR) have been increasingly used in renal transplantation as part of calcineurin inhibitor (CNI) sparing or avoidance regimens. Those drugs have low and variable oral bioavailability that is increased when combined with cyclosporine or tacrolimus (TAC). We investigated the mechanisms invo...
