Benoit Blanchet

Assistance Publique – Hôpitaux de Paris | AP-HP · Laboratory of pharmacology

159 Background: Abiraterone acetate (ABI) improves survival in mCRPC. In a previous observational study, worse PSA response and shorter progression-free survival (PFS) were associated with mean ABI plasma through concentration (ABI Cmin) < 8.5 ng/mL within the first three months (ms) of treatment (Carton E et al. Eur J Cancer 2017). The OPTIMABI st...

676 Background: At the recommended dose of 60mg/day in mRCC, CABO is associated with frequent and/or severe toxicities in mRCC, which may be modified, along with clinical benefit, by interindividual variability in pharmacokinetics (PK). The objective of this multicentre ambispective study was to determine whether the PK of CABO could help to better...

Steroidogenesis inhibitors such as metyrapone (MTP) and osilodrostat (ODT) have a key role in the medical treatment of endogenous Cushing's Syndrome (ECS). Both drugs are characterized by a high inter-individual variability of response and require a dose-titration period to achieve optimal control of cortisol excess. However, PK/PD data remain scar...

This case report describes of a pharmacokinetic drug–drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct‐acting antiviral drug, leading to cardiac toxicity. A 75‐year‐old man, with no cardiovascular history but a diagnosis of metastatic non‐small cell lung cancer with MET exon‐14 deletion and hepat...

Seven tyrosine kinase inhibitor compounds with anti-angiogenic properties remain key drugs to treat advanced renal cell carcinoma. There is a strong rationale to develop therapeutic drug monitoring for these drugs. General considerations of such monitoring of the several groups of anticancer drugs are given, with a focus on oral therapy. Pharmacoki...

Introduction La variabilité interindividuelle de la réponse clinique et biologique au rituximab (RTX) reste inexpliquée chez les patients atteints de vascularite associée aux ANCA. La pharmacocinétique (PK) et la pharmacodynamique (PD) du RTX, ainsi que certains polymorphismes génétiques, pourraient contribuer à cette variabilité. Cette étude auxil...

Objectif L’osilodrostat est, comme la métyrapone, un inhibiteur de la CYP11B1, utilisé dans le traitement du syndrome de Cushing (SC). L’objectif de cette étude était de comparer les profils stéroïdiens sériques des patients traités par osilodrostat ou métyrapone pour un SC ACTH-dépendant. Matériels et méthodes L’ensemble des patients suivis dans...

Purpose The efficacy of antimalarials, especially hydroxychloroquine (HCQ), in preventing flares of systemic lupus erythematosus (SLE) is well demonstrated, but its effectiveness is impaired by non-adherence to treatment, reported to vary between 3% and 85%.We aimed to assess the associations of baseline severe non-adherence to HCQ, objectively ass...

High interindividual variability (IIV) of the clinical response to epidermal growth factor receptor (EGFR) inhibitors such as osimertinib in non-small-cell lung cancer (NSCLC) might be related to the IIV in plasma exposure. The aim of this study was to evaluate the exposure–response relationship for toxicity and efficacy of osimertinib in unselecte...

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic–pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mec...

Regulators of TLRs signaling pathways play an important role in the control of the pro-inflammatory response that contributes to sepsis-induced tissue injury. Mycophenolate mofetil, an immunosuppressive drug inhibiting lymphocyte proliferation, has been reported to be a regulator of TLRs signaling pathways. Whether MMF used at infra-immunosuppressi...

This case report describes of a pharmacokinetic drug–drug interaction between crizotinib, a tyrosine kinase inhibitor, and sofosbuvir/velpatasvir, a direct-acting antiviral drug, leading to cardiac toxicity. A 75-year-old man, with no cardiovascular history but a diagnosis of metastatic non-small cell lung cancer with MET exon-14 deletion and hepat...

Background: This study compared the performance of plasma infliximab and adalimumab quantification using a commercially available kit (mAbXmise kit) and mass spectrometry readout to that of two ELISA methods in patients treated for inflammatory bowel disease. Methods & results: The mAbXmise method based on liquid chromatography tandem mass spectrom...

Implementing PK-guided dosing with monoclonal antibodies (mAbs) in oncology has been for long impaired by difficulties in developing appropriate (i.e., time- and cost-effective) bioanalytical methods suitable for routine Therapeutic Drug Monitoring, plus concerns regarding the exact PK/PD relationships of several biologics possibly blurred by the T...

Introduction: Osilodrostat is a new 11 ß-hydroxylase inhibitor with a mode of action analogue to Metyrapone. The objective of this study was to compare steroidogenic profiles in patients treated by either Osilodrostat or Metyrapone for ACTH-dependent Cushing’s Syndrome (CS). Methods: Patients followed in Cochin hospital Endocrinology department bet...

Introduction L’efficacité de l’hydroxychloroquine (HCQ) dans la prévention des poussées de lupus systémique (LS) est altérée par la non-adhésion au traitement, qui varierait entre 3 % et 85 % selon les études. L’objectif était d’évaluer l’association entre la non-adhésion sévère au traitement par HCQ définie par dosage sanguin et les risques de pou...

Background. Pazopanib is an oral angiogenesis inhibitor approved to treat soft tissue sarcoma (STS) but associated with large interpatient pharmacokinetic (PK) variability and narrow therapeutic index. In order to improve its clinical use, this study aimed to define specific threshold of pazopanib trough concentration (Cmin) associated with better...

Background The risk of drug–drug interactions (DDI) has become a major issue in cancer patients. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency and the factors associated with DDI with antitumor treatments, and to evaluate the impact of a pharmacist evaluation before anticancer treatment.Patients and methodsWe perf...

Background. Pazopanib (PAZ) is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma (RCC) and soft tissue sarcoma (STS). A relationship was reported between PAZ trough concentration (Cmin) and progression free survival (PFS) in RCC (Suttle A.B. 2015; Verheijen R.B. 2017). However, information on the exposure-efficacy relatio...

Factors associated with olaparib toxicity remain unknown in ovarian cancer patients. The large inter-individual variability in olaparib pharmacokinetics could contribute to the onset of early significant adverse events (SAE). We aimed to retrospectively analyze the pharmacokinetic/pharmacodynamic relationship for toxicity in ovarian cancer patients...

Background: Different liquid chromatography tandem mass spectrometry (LC-MS/MS) methods have been published for quantification of monoclonal antibodies (mAbs) in plasma but thus far none allowed the simultaneous quantification of several mAbs, including immune checkpoint inhibitors. We developed and validated an original multiplex LC-MS/MS method...

Pembrolizumab is a humanized immunoglobulin G4-kappa anti-PD1 antibody used in the treatment of different solid tumors or haematological malignancies. A liquid chromatography coupled with a high resolution mass spectrometry (orbitrap technology) method was fully developed, optimized, and validated for quantitative analysis of pembrolizumab in human...

Rituximab is a chimeric immunoglobulin G1-kappa (IgG1κ) antibody targeting the CD20 antigen on B-lymphocytes. Its applications are various, such as for the treatment of chronic lymphoid leukemia or non-Hodgkin’s lymphoma in oncology, and it can also be used in the treatment of certain autoimmune diseases. Several studies support the interest in the...

Background: The risk of drug drug interactions (DDI) has become a major issue in cancer patient care. However, data in sarcoma patients are scarce. We aimed to evaluate the frequency of DDI with antitumor treatments, identify the risk factors for DDI and evaluate the impact of a pharmacist evaluation before anticancer treatment. Patients and Method...

Introduction Le traitement du mélanome métastatique muté BRAF par dabrafénib en association avec le tramétinib se caractérise par une importante variabilité interindividuelle de la réponse clinique. Les objectifs de cette étude étaient d’étudier l’exposition plasmatique (aire sous la courbe, ASC) du dabrafénib (DAB), de son métabolite actif, l’hydr...

Nivolumab is a fully human immunoglobulin G4 used for the treatment of several advanced solid cancers as immune checkpoint inhibitors. There are some challenges for the quantification of mAb in plasma because IgG are present intrinsically in complex biologic matrices and this determination must be based on reliable, selective, and accurate analytic...

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation w...

Background: Hydroxychloroquine (HCQ) levels can be measured in both serum and whole blood. No cut-off point for non-adherence has been established in serum nor have these methods ever been compared. The aims of this study were to compare these two approaches and determine if serum HCQ cut-off points can be established to identify non-adherent pati...

Objective To explore pharmacokinetic/pharmacodynamic relationship between mycophenolic acid area under the curve and clinical response at 1 year on skin involvement or interstitial lung disease in patients with systemic sclerosis. Method Retrospective, monocentric study based on French Scleroderma Database in patients receiving mycophenolate mofet...

Purpose Erlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non–small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were t...

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure–response relationship for toxicity and efficacy in metastatic mela...

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...

Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved catabolic process whose loss-of-function has been linked to a growing list of pathologies. Knockout mouse models of key autophagy genes have been instrumental in the demonstration of the critical functions of autophagy, but they display early lethality, neurotoxicity...

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with su...

A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then f...

Background: The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological paramet...

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small–cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma tr...

Background Nintedanib is a multikinase inhibitor whose main targets are VEGFR 1/2/3, PDGFR and FGFR1. It is approved for idiopathic pulmonary fibrosis and non-small-cell lung cancer. The randomized phase II CHIVA trial tested it as an add-on to chemotherapy in the neo-adjuvant/adjuvant setting in advanced ovarian cancer eligible for debulking surge...

Purpose: Therapeutic response to oral targeted anticancer protein kinase inhibitors (PKIs) varies widely between patients, with insufficient efficacy of some of them and unacceptable adverse reactions of others. There are several possible causes for this heterogeneity, such as pharmacokinetic variability affecting blood concentrations, fluctuating...

Context Anti-PD1 therapy nivolumab has been approved for the treatment of advanced non-small cell lung cancer (NSCLC). However, a large inter-individual variability in its efficacy has been observed. Thus, the search for reliable factors to predict anti-PD1 efficacy represents a major challenge, particularly in NSCLC patients. The aim of this prosp...

Context Anti-PD1 therapy nivolumab has been approved for the treatment of advanced non-small cell lung cancer (NSCLC). However, a large inter-individual variability in its efficacy has been observed. Thus, the search for reliable factors to predict anti-PD1 efficacy represents a major challenge, particularly in NSCLC patients. The aim of this prosp...

Background In order to assess the pharmacokinetic/pharmacodynamic relationship of hydroxychloroquine (HCQ) in patients with systemic lupus erythematosus (SLE), HCQ levels have been measured in whole blood as well as in serum but both methods have never been compared. In addition, cut offs for non-adherence (classically 200ng/ml but also 100 ng/mL)...

Background The usefulness of very low hydroxychloroquine (HCQ) blood levels to unmask severe non-adherence in patients with systemic lupus erythematosus (SLE) has been established, including in a recent prospective study. However, little is known on the individual impact of HCQ blood levels measurement. Objectives To assess the impact of HCQ blood...

Introduction: Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metaboli...

In the era of precision medicine, research of biomarkers for identification of responders to nivolumab therapy is a major challenge. Peripheral blood mononuclear cells (PBMC) could be an interesting surrogate tissue for identifying pharmacodynamic biomarkers. The aim of this exploratory study was to investigate the global serine/threonine kinase (S...

Purpose: Limited published data are available regarding the pharmacokinetic (PK) and pharmacodynamic (PD) variables of prolonged-release tacrolimus (PRT) after liver transplantations. The goal of this study was to compare the PK and PD profiles of PRT in early and stable liver transplant recipients by developing a population PK model of PRT and in...

Aims: Cytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this...

Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug–drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresist...

Résumé Les thérapies ciblées orales sont une classe de médicaments anti-tumoraux en pleine expansion. À l’issue d’essais cliniques menés sur des populations sélectionnées, ces molécules sont approuvées le plus souvent selon une posologie unique. Pourtant, elles présentent une grande variabilité pharmacocinétique inter et intra-individuelle, et un i...

Le corticosurrénalome est un cancer peu chimiosensible. L’association mitotane et chimiothérapie par platine-étoposide constitue le standard thérapeutique en première ligne métastatique. Le mitotane est un puissant inducteur du CYP3A4 de la BCRP et pourrait interagir avec l’étoposide (susbtrat du CYP3A4 et BCRP), et limiter son efficacité. Objecti...

Measuring tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMC) could better reflect the drug effect on its target (calcineurin (CaN) in lymphocytes) than whole blood concentrations. Mechanisms influencing TAC diffusion into PBMC are not well characterized. This work aimed at describing, ex‐vivo, TAC diffusion kinetics into PB...

Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAFV600E mut...

Δ⁴-abiraterone (Δ4A) is an activemetabolite of abiraterone (ABI), which is approved in the treatment of metastatic castration resistant prostate cancer (mCRPC). The contribution of Δ4A to the clinical antitumor activity of ABI remains unknown. The aim of this study was to explore the relationship between plasma Δ4A concentration and survival in 36...

The use of anticoagulants in patients with cancer is challenging as several co-morbidities modifying pharmacokinetic (PK) parameters and significant drug-drug interactions with concomitant anti-neoplastic therapies may lead to PK variability resulting in increased risk of thrombosis or bleeding. Data on the management of patients with cancer-associ...

Background : Abiraterone (ABI), a steroidal CYP17A1 inhibitor, blocks the DHT synthesis from adrenal precursor steroids in castration resistant prostate cancer (mCRPC) patients. ABI is converted by 3β-hydroxysteroid dehydrogenase (HSD3B) into D4-abiraterone (D4-ABI). In a previous preclinical study, D4-ABI was shown to block multiple steroidogenic...

Introduction Nous présentons un cas de toxicité cutanée secondaire à une surexposition en tramétinib, iMEK, administré en monothérapie pour un mélanome métastatique muté NRAS. Observations Une femme de 75 ans présentait un cancer du sein métastatique traité par capécitabine et un mélanome métastatique stade IV BRAF sauvage NRAS muté, progressant s...

THe aim of that study is to study the relationship between TAC intra-PBMC trough concentrations, calcineurin activity in PBMC and TAC whole blood trough concentrations in liver transplant recipients within the 6 months post transplantation

Tyrosine kinase inhibitors (TKIs) used in the treatment of metastatic renal cell carcinoma present high interindividual variability in clinical response and toxicity. In addition, high interindividual variability in pharmacokinetics (PK) of TKIs is observed which could explain therapeutic failure or elevated toxicity in some patients. Monitoring of...

Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3-4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients tr...

Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentri...