Jean-Baptiste Woillard

Centre Hospitalier Universitaire de Limoges · Department of Pharmacology, Toxicology and Pharmacovigilance

Purpose To demonstrate the effective integration of pharmacometrics and pharmacovigilance in managing medication errors, highlighted by a case involving secukinumab in a patient with hidradenitis suppurativa. Methods We present the case of a 41-year-old male with progressive hidradenitis suppurativa, unresponsive to multiple antibiotic regimens an...

Background Mycophenolic acid is widely used to treat lupus nephritis (LN). However, it exhibits complex pharmacokinetics with large interindividual variability. This study aimed to develop a population pharmacokinetic (popPK) model and a 3-sample limited sampling strategy (LSS) to optimize therapeutic drug monitoring in Indian patients with LN. Me...

Daptomycin is a concentration-dependent lipopeptide antibiotic for which exposure/effect relationships have been shown. Machine learning (ML) algorithms, developed to predict the individual exposure to drugs, have shown very good performances in comparison to maximum a posteriori Bayesian estimation (MAP-BE). The aim of this work was to predict the...

Ganciclovir (GCV) and valganciclovir (VGCV) show large interindividual pharmacokinetic variability, particularly in children. The objectives of this study were (1) to develop machine learning (ML) algorithms trained on simulated pharmacokinetics profiles obtained by Monte Carlo simulations to estimate the best ganciclovir or valganciclovir starting...

Background This study aimed to evaluate the concentrations of rilpivirine (RLP) and doravirine (DOR) after 3 days-off using simulations from population pharmacokinetics models. Methods The authors conducted a series of 500 sets of 10,000 Monte Carlo simulations to examine the steady-state conditions for 2 common dosage levels: 25 mg/d for RLP and...

Background Acute cor pulmonale (ACP) is prognostic in patients with acute respiratory distress syndrome (ARDS). Identification of paradoxical septal motion (PSM) using two-dimensional echocardiography is highly subjective. We sought to describe feature-engineered metrics derived from LV radial strain changes related to PSM in ARDS patients with ACP...

Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is widely used in the treatment of systemic lupus erythematosus (SLE). It has been shown that its therapeutic drug monitoring based on the area under the curve (AUC) improves treatment efficacy. MPA exhibits a complex bimodal absorption, and a double gamma distribution m...

Precision medicine requires individualized modeling of disease and drug dynamics, with machine learning-based computational techniques gaining increasing popularity. The complexity of either field, however, makes current pharmacological problems opaque to machine learning practitioners, and state-of-the-art machine learning methods inaccessible to...

Introduction Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be hig...

Introduction Tacrolimus is an immunosuppressant largely used in heart transplantation. However, the calculation of its exposure based on the area under the curve (AUC) requires the use of a population pharmacokinetic (PK) model. The aims of this work were (i) to develop a population PK model for tacrolimus in heart transplant patients, (ii) to deri...

LCP-tacrolimus displays enhanced oral bioavailability compared to immediate-release (IR-) tacrolimus. The ENVARSWITCH study aimed to compare tacrolimus AUC0-24 h in stable kidney (KTR) and liver transplant recipients (LTR) on IR-tacrolimus converted to LCP-tacrolimus, in order to re-evaluate the 1:0.7 dose ratio recommended in the context of a swit...

Objectives 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 ind...

In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) in therapeutic drug monitorin...

Background: The Immunosuppressant Bayesian Dose Adjustment web site aids clinicians and pharmacologists involved in the care of transplant recipients; it proposes dose adjustments based on the estimated area under the concentration-time curve (AUCs). Three concentrations (T20 min, T1 h, and T3 h) are sufficient to estimate mycophenolic acid (MPA)...

Purpose: Tacrolimus is an immunosuppressant widely used in transplantations requiring mandatory concentration-controlled dosing to prevent acute rejection or adverse effects, including new-onset diabetes mellitus (NODM). However, no relationship between NODM and tacrolimus exposure has been established. This study aimed to evaluate the relationshi...

Background: The authors report the case of a 66-year-old male patient who was hemodialyzed 3 times per week for chronic renal failure and treated with 100 mg of doravirine once daily in combination with dolutegravir for HIV-1. No dose adjustment is required for doravirine in cases of severe renal injury, but the effect of dialysis on its exposure...

Background: The aim of this work was to evaluate, in a large data set of renal transplant recipients, the intraindividual variability of the area under the curve (AUC)/predose concentration (C0) ratio in comparison with that of AUC, C0, AUC/dose, and C0/dose. Methods: Patients with at least 2 tacrolimus AUC estimation requests were extracted fro...

Purpose Machine Learning (ML) algorithms represent an interesting alternative to maximum a posteriori Bayesian estimators (MAP-BE) for tacrolimus AUC estimation, but it is not known if training an ML model using a lower number of full pharmacokinetic (PK) profiles (= “true” reference AUC) provides better performances than using a larger dataset of...

Slow-flow vascular malformations (VMs), especially those with venous components, can be complicated by localized intravascular coagulopathy (LIC), responsible for pain and impaired quality of life. Several studies have shown the effectiveness of mTOR inhibitors (especially sirolimus) on slow-flow VMs but its effect on coagulation has been poorly st...

Interpretation of kidney graft biopsies using the Banff classification is still heterogeneous. In this study, extreme gradient boosting classifiers learned from two large training datasets (n= 631 and 304 cases) where the “reference diagnoses” were not strictly defined following the Banff rules but from central reading by expert pathologists and fu...

Background: Renal failure is an independent prognostic factor for survival in patients with cirrhosis. Equations to calculate serum creatinine significantly overestimate the glomerular filtration rate (GFR). Plasma clearance of direct biomarkers has been used to improve the accuracy of evaluations of GFR in this population, but no study has simult...

Introduction Vancomycin is one of the antibiotics most used in neonates. Continuous infusion has many advantages over intermittent infusions, but no consensus has been achieved regarding the optimal initial dose. The objectives of this study were: to develop a Machine learning (ML) algorithm based on pharmacokinetic profiles obtained by Monte Carlo...

Introduction Mycophenolate mofetil (MMF), a pro-drug of mycophenolic acid (MPA), has become a major therapeutic option in juvenile systemic lupus erythematosus (jSLE). Monitoring MPA exposure using area under curve (AUC) has proved its value to increase efficacy and safety in solid organ transplantation both in children and adults, but additional d...

Background: Maximum a posteriori Bayesian estimation (MAP-BE) based on a limited sampling strategy and a population pharmacokinetic model is frequently used to estimate pharmacokinetic parameters in individuals, however with some uncertainty (bias). Recent works have shown that the performance in individual estimation or pharmacokinetic parameters...

Aims Mycophenolate mofetil (MMF) is the most widely used second‐line agent in autoimmune hepatitis (AIH). Individual dose adjustment of MMF may avoid adverse outcomes while maximizing efficacy. The aim of the present study was to develop population pharmacokinetic (popPK) models and maximum a posteriori Bayesian estimators (MAP‐BEs) to estimate myc...

Everolimus is an immunosuppressant with a small therapeutic index and large between‐patient variability. The area under the concentration versus time curve (AUC) is the best marker of exposure but measuring it requires collecting many blood samples. The objective of this study was to train machine learning (ML) algorithms using pharmacokinetic (PK)...

Introduction Estimation of vancomycin area under the curve (AUC) is challenging in the case of discontinuous administration. Machine learning approaches are increasingly used and can be an alternative to population pharmacokinetic (POPPK) approaches for AUC estimation. The objectives were to train XGBoost algorithms based on simulations performed i...

Aims Iohexol clearance has been proposed to estimate the glomerular filtration rate (GFR). A population pharmacokinetics (popPK) model was developed from heterogeneous patients. A Bayesian estimator (MAP‐BE) based on a limited sampling strategy (LSS) was derived and evaluated in external patients. Methods Full pharmacokinetic data (7–12 samples) f...

Introduction Le sirolimus, inhibiteur de mTOR, est de plus en plus souvent utilisé pour traiter différentes anomalies vasculaires. Les publications comprennent toutefois essentiellement des données observationnelles. L’objectif de cette étude a été d’évaluer, par une étude contrôlée, l’efficacité et la sécurité du sirolimus pour traiter les malform...

Background: Mycophenolate mofetil (MMF) is the most widely used second-line agent in auto-immune hepatitis (AIH). It is generally titrated up to patient response and continued for at least two years following complete liver enzyme normalization. However, in this maintenance phase individual dose adjustment to reach mycophenolic acid (MPA) exposure...

Population pharmacokinetics consists in analyzing pharmacokinetic (PK) data collected in groups of individuals. Population PK is widely used to guide drug development and to inform dose adjustment via therapeutic drug monitoring (TDM) and model‐informed precision dosing (MIPD). There are two main types of population PK methods: parametric (P) and n...

Ganciclovir (GCV) and valganciclovir (VGCV) are first choice drugs for the prevention and treatment of cytomegalovirus infection and disease in solid organ and stem cell transplant recipients. Only a few studies on the pharmacokinetics and exposure/efficacy or exposure/safety relationships of ganciclovir and valganciclovir in transplant recipients...

Background: The Banff classification standardizes the diagnoses of kidney transplant rejection based on histological criteria. Clinical decisions are generally made after integration of the Banff diagnoses in the clinical context. However, interpretation of the biopsy cases is still heterogeneous among pathologists or clinicians. Machine Learning (...

Importance: Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking. Objective: To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment. Design, setting and participants: This multicenter, o...

Background and Objective Given a high pharmacokinetic inter-individual variability and a low exposure target achievement, ganciclovir (GCV) therapeutic drug monitoring is sometimes used in children. We aimed to develop and validate Bayesian estimators based on limited sampling strategies for the estimation of GCV area under the concentration–time c...

Background Mycophenolate mofetil (MMF) is theoretically a treatment of choice for Mucous Membrane Pemphigoid (MMP), due to its good long‐term tolerance and efficacy especially in elderly patients. However, no therapeutic monitoring is currently performed despite its large inter‐individual variability. Objectives The aim of this study was to invest...

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...

We previously demonstrated that Machine learning (ML) algorithms can accurately estimate drug area under the curve (AUC) of tacrolimus or mycophenolate mofetil (MMF) based on limited information, as well as or even better than maximum a posteriori Bayesian estimation (MAP-BE). However, the major limitation in the development of such ML algorithms i...

The demand for organs to be transplanted increases pressure on procurement centers, to the detriment of organ quality, increasing complications. New preservation protocols are urgently needed, requiring an in-depth understanding of ischemia-reperfusion mechanisms. We performed a proteomic analysis using LC-MS/MS-TOF data analyzed through R software...

Therapeutic drug monitoring of mycophenolic acid (MPA) based on area under the curve (AUC) is well established and machine learning (ML) approaches could help to estimate AUC. The aim of this work is to estimate the AUC of MPA in organ transplant patients using Xgboost ML models. A total of 12,877 MPA AUC0‐12h requests from 6884 patients sent to ou...

Aims Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are first‐line agents to prevent and treat cytomegalovirus in transplant recipients. There is high pharmacokinetic (PK) interindividual variability and PK data are scarce, especially in paediatric stem cell transplant (SCT) recipients. We sought to determine the optimal GCV and VGCV dosin...

Aims To develop a pharmacokinetic model of isoniazid (INH) concentration taking into account demographic factors and genetic variables (N-acetyltransferase 2 (NAT2) genotype) and to propose an initial INH dosage that could maximize the probability of achieving desired INH concentrations. Methods We performed a retrospective analysis of INH concent...

Background: In children with cystic fibrosis (CF), the currently recommended amikacin dose ranges between 30 and 35 mg/kg/d; however, data supporting this dosing efficacy are lacking. In this article, the objectives were to develop a nonparametric pharmacokinetic population model for amikacin in children with CF and investigate the efficacy and to...

The aim of this work is to estimate the area‐under the blood concentration curve of tacrolimus following twice‐a‐day (BID) or once‐a‐day (QD) dosing in organ transplant patients, using Xgboost machine learning (ML) models. A total of 4997 and 1452 tacrolimus inter‐dose AUCs from patients on BID and QD tacrolimus, sent to our ISBA expert system (www...

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...

Background: Immunosuppressant Bayesian Dose Adjustment (ISBA) is an online expert system that estimates the area under the curve (AUC) of immunosuppressive drugs through pharmacokinetic modelling and Bayesian estimation to propose dose adjustments to reach predefined exposure targets. The ISBA database was retrospectively analyzed to describe tacr...

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...

Population pharmacokinetic (PK) modeling is a widely used approach to analyze PK data obtained from groups of individuals, in both industry and academic research. The approach can also be used to analyze pharmacodynamic (PD) data and pooled PK/PD data. There are 2 main families of population PK methods: parametric and nonparametric. The objectives...

Background Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce.Methods Retrospective study of 27...

Objective This work aims to evaluate whether a machine learning approach is appropriate to estimate the glomerular filtration rate in intensive care unit patients based on sparse iohexol pharmacokinetic data and a limited number of predictors.Methods Eighty-six unstable patients received 3250 mg of iohexol intravenously and had nine blood samples c...

Therapeutic drug monitoring (TDM) is mandatory for the immunosuppressive drug tacrolimus (Tac). For clinical applicability, TDM is performed using morning trough concentrations. With recent developments making tacrolimus concentration determination possible in capillary microsamples and Bayesian estimator predicted area under the concentration curv...

PurposeThe usual recommended dose for gentamicin is 3 to 7 mg/kg/day for patients with a normal renal function while 1.7 mg/kg/day is recommended for patients undergoing chronic haemodialysis. The objectives of this study were to develop a population pharmacokinetics model (POPPK) for gentamicin, designed for patients undergoing dialysis, and to in...

An 83-year-old man, presenting decreased renal function (estimated glomerular filtration rate 21 mL/min/1.73 m), was treated for a bone and joint infection (on a trans-metatarsal right foot amputation) caused by Klebsiella Pneumonia sensitive to cefepime. The starting dose (1 g bid) was based on recommendations for patients presenting severe infect...

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...

Tacrolimus (TAC) is the cornerstone of immunosuppressive therapy in liver transplantation. This study aimed at elucidating the interplay between pharmacogenetic determinants of TAC whole blood and intracellular exposures as well as the pharmacokinetic-pharmacodynamic relationship of TAC in both compartments. Complete pharmacokinetic profiles (Predo...

Aims Intravenous mycophenolate mofetil (IV MMF), a prodrug of mycophenolic acid (MPA), is used during nonmyeloablative and reduced‐intensity conditioning haematopoetic stem cell transplantation (HCT) to improve engraftment and reduce graft‐versus‐host disease. The aims of this study were to develop population pharmacokinetic models and Bayesian est...

Purpose In critically ill patients treated with meropenem, the proposed pharmacokinetics/pharmacodynamics (PK/PD) efficacy index is to keep the free drug concentration 4–5 times above the minimum inhibitory concentration (MIC) of the germ isolated, for 100% of the interval regimen. The objectives were to design a population pharmacokinetics model f...

Aims: Tacrolimus is a narrow therapeutic range drug that requires fine dose adjustment, for which pharmacokinetic (PK) models have been amply proposed in renal, but not in liver, transplant recipients. This study aimed to build population PK models and Bayesian estimators (BEs) in adult de novo liver transplant patients receiving either the immedia...

PS2-025 : This study showed clearly the usefulness of genotyping of CYP3A4*1B CYP3A4*22 and CYP3A5*3 in the Tac TDM optimization in Tunisian renal graft patients

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...

Tacrolimus is the milestone in pediatric liver transplant immunosuppression. Despite close monitoring, fluctuations in tacrolimus blood levels affect safety and efficacy of immunosuppressive treatments. Identifying the factors related to the variability in tacrolimus exposure may be helpful in tailoring the dose. The aim of the present study was to...

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...

Everolimus is a mammalian target of rapamycin (m-TOR) inhibitor that has been approved for the treatment of hormone receptor-positive advanced breast cancer, metastatic renal cancer, and neuroendocrine tumors. Although therapeutic drug monitoring (TDM) of everolimus is well established in the transplantation field, it is not currently performed in...

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...

Background Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history i...

Background: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individ...

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...

Background and objective: Intracellular exposure of everolimus may be a better marker of therapeutic effect than trough whole blood concentrations. We aimed to develop pharmacokinetic population models and Bayesian estimators based on a limited sampling strategy for estimation of dose interval exposures of everolimus in whole blood and peripheral...

Morbid obesity is known to increase the risk of surgical site infections. Optimal concentrations of prophylactic antibacterial drugs are required. Using Monte Carlo simulations, the aim of this work was to build a population pharmacokinetics model for a morbidly obese population to assess a 4000-mg dose of cefazolin recommended by the guidelines an...

Background: ISBA is an online expert system, routinely used by approximately 140 transplantation centers in the world for the dose adjustment of immunosuppressive drugs in transplant patients. This system determines the drug area-under-the-curve (AUC) by PK modeling and Bayesian estimation. The purpose of this study was to analyze tacrolimus expos...

Due to a high inter-individual variability in its pharmacokinetics, tacrolimus dose individualization is mandatory. Even though the expert opinion has defined the area under the curve (AUC) as the best marker to use when performing dose adjustment of tacrolimus, most centres only use trough levels. Multiple targets have been proposed for this param...

Although OATP1B1 is not expressed in the kidney, polymorphisms in SLCO1B1 have been associated with methotrexate clearance or toxicity. This unexpected pharmacogenetic association may reflect remote communication between liver and kidney transporters. This study confirms the pharmacogenetic association with methotrexate toxicity in adult patients w...

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...

Background: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated...

Introduction Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is an effective treatment in lupus nephritis. Therapeutic drug monitoring studies of MMF suggest that area under the concentration-time curve (AUC) values of MPA of 30–45 mg.h/L may be associated with better outcome in adults with lupus but data in children...

Background Pain and its opioid treatments are complex measurable traits. Responses to morphine in terms of pain control is likely to be determined by many factors, including the underlying pain sensitivity of the patient, along with nature and extent of the painful process, concomitant medications, genetic and other clinical and environmental facto...

Background: We sought to evaluate, in patients on a liver transplantation waiting list, potential biomarkers of the base calcineurin pathway activity with use of a new model of nonstimulated peripheral blood mononuclear cells (PBMC) and ex vivo response to tacrolimus (TAC). Methods: The calcineurin pathway activity was explored ex vivo in stimul...

Background Patients’ experiences of immunosuppressive treatment, including their perception of adverse effects, influences their quality of life and may be a trigger for poor adherence. The Medication Experience Scale for Immunosuppressants (MESI) questionnaire was designed in German to evaluate patients’ experiences of immunosuppressive drugs. Ob...

Tacrolimus (Tac) is a profoundly effective immunosuppressant that reduces the risk of rejection after solid organ transplantation. However, its use is hampered by its narrow therapeutic window along with its highly variable pharmacological (pharmacokinetic [PK] and pharmacodynamic [PD]) profile. Part of this variability is explained by genetic poly...

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...