Publications by authors named "Benoit Blanchet"

94 Publications

Effects of acyl-coenzyme A binding protein (ACBP)/diazepam-binding inhibitor (DBI) on body mass index.

Cell Death Dis 2021 Jun 9;12(6):599. Epub 2021 Jun 9.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université de Paris, Sorbonne Université, Paris, France.

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor acyl-coenzyme A binding protein (ACBP, also called diazepam-binding inhibitor, DBI) acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. Here, we show that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3-9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels. Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.
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http://dx.doi.org/10.1038/s41419-021-03864-9DOI Listing
June 2021

Analysis of Pembrolizumab in Human Plasma by LC-MS/HRMS. Method Validation and Comparison with Elisa.

Biomedicines 2021 May 30;9(6). Epub 2021 May 30.

Biochemistry and Pharmacology-Toxicology Laboratory, Lyon-Sud Hospital, Hospices Civils de Lyon, F-69495 Pierre Bénite, France.

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 plasma. A mass spectrometry assay was used for the first time a full-length stable isotope-labelled pembrolizumab-like (Arginine C-N and Lysine C-N) as an internal standard; the sample preparation was based on albumin depletion and trypsin digestion and, finally, one surrogate peptide was quantified in positive mode. The assay showed good linearity over the range of 1-100 μg/mL, a limit of quantification at 1 μg/mL, excellent accuracy from 4.4% to 5.1%, and also a between-day precision below 20% at the limit of quantification. In parallel, an in-house ELISA was developed with a linearity range from 2.5 to 50 µg/mL. Then, results were obtained from 70 plasma samples of cancer patients that were treated with pembrolizumab and quantified with both methods were compared using the Passing-Bablok regression analysis and Bland-Altman plotting. The LC-MS/HRMS method is easy to implement in the laboratory for use in the context of PK/PD studies, clinical trials, or therapeutic drug monitoring.
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http://dx.doi.org/10.3390/biomedicines9060621DOI Listing
May 2021

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Mol Pharmacol 2021 May 14. Epub 2021 May 14.

Centre de Recherche des Cordeliers, INSERM UMRS1138, France

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multi-target inhibitor sorafenib is a first-line treatment for patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the anti-diabetic drug metformin have a survival disadvantage compared to patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg/d) could influence the antitumoral effects of sorafenib (15 mg/kg/d) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, concomitant sequential dosing regimens. We observed that the administration of metformin six hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. When drugs are administrated sequentially, metformin alters the anti-tumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMPK pathway as well as major transcriptomic changes are associated with the loss of the anti-tumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were co-treated with metformin and sorafenib.
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http://dx.doi.org/10.1124/molpharm.120.000223DOI Listing
May 2021

Development, Validation, and Comparison of Two Mass Spectrometry Methods (LC-MS/HRMS and LC-MS/MS) for the Quantification of Rituximab in Human Plasma.

Molecules 2021 Mar 4;26(5). Epub 2021 Mar 4.

Biochemistry and Pharmacology-Toxicology Laboratory, Lyon-Sud Hospital, Hospices Civils de Lyon, F-69495 Pierre Bénite, France.

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 therapeutic drug monitoring to optimize dosing regimens of rituximab. Thus, two different laboratories have developed accurate and reproductive methods to quantify rituximab in human plasma: one using liquid chromatography quadripolar tandem mass spectrometer (LC-MS/MS) and the other, liquid chromatography orbitrap tandem mass spectrometer (LC-MS/HRMS). For both assays, quantification was based on albumin depletion or IgG-immunocapture, surrogate peptide analysis, and full-length stable isotope-labeled rituximab. With LC-MS/MS, the concentration range was from 5 to 500 µg/mL, the within- and between-run precisions were <8.5%, and the limit of quantitation was 5 µg/mL. With LC-MS/HRMS, the concentration range was from 10 to 200 µg/mL, the within- and between-run accuracy were <11.5%, and the limit of quantitation was 2 µg/mL. Rituximab plasma concentrations from 63 patients treated for vasculitis were compared. Bland-Altman analysis and Passing-Bablok regression showed the interchangeability between these two methods. Overall, these methods were robust and reliable and could be applied to routine clinical samples.
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http://dx.doi.org/10.3390/molecules26051383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961417PMC
March 2021

Quantification of nivolumab in human plasma by LC-MS/HRMS and LC-MS/MS, comparison with ELISA.

Talanta 2021 Mar 12;224:121889. Epub 2020 Nov 12.

Laboratoire de Biochimie et Pharmaco-toxicologie, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, F-69495, Pierre Bénite, France; EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine Lyon-Sud, F-69921, Oullins, France; Laboratoire de Toxicologie, Faculté de Pharmacie ISPBL, Université Lyon 1, F-69373, Lyon, France. Electronic address:

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 analytical methods. This study described two validated methods carried out in two separate laboratories, one developed with a triple quadrupole tandem mass spectrometry (LC-MS/MS) and the other with high resolution mass spectrometry with an orbitrap system (LC-MS/HRMS). Both methods used full-length stable isotope-labeled nivolumab-like (Arginine C6-N and Lysine C-N) as internal standard. The sample preparation was based on IgG immunocapture, then trypsin digestion was performed and one surrogate peptide was quantified in positive mode. Assays showed good linearity over the range of 5-100 μg/mL and 5-150 μg/mL for LC-MS/HRMS and LC-MS/MS, respectively. The limit of quantification was set at 2 and 5 μg/mL for LC-MS/HRMS and LC-MS/MS, respectively. Acceptable accuracy (from - 13.6% to 3.0%) and precision (within 20%) values were also obtained with both methods. The two LC-MS methods showed a very different matrix effect linked to the use of different analytical columns and elution gradients. Nivolumab plasma concentrations from 60 cancer outpatients were compared with the two mass spectrometry methods and also with a home-made ELISA method. The Bland-Altman analysis did not show any significant bias between the three methods. The Passing-Bablock linear regression analysis showed a good agreement between the three methods with a better correlation between the two mass spectrometry methods.
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http://dx.doi.org/10.1016/j.talanta.2020.121889DOI Listing
March 2021

Simultaneous quantification of dabrafenib, hydroxy-dabrafenib and trametinib in human plasma by liquid chromatography-tandem mass spectrometry.

J Pharm Biomed Anal 2021 Jan 27;193:113718. Epub 2020 Oct 27.

Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University of Paris, PRES Sorbonne Paris Cité, CARPEM, 75006 Paris, France.

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 with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 μL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer.
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http://dx.doi.org/10.1016/j.jpba.2020.113718DOI Listing
January 2021

Hydroxychloroquine levels in patients with systemic lupus erythematosus: whole blood is preferable but serum levels also detect non-adherence.

Arthritis Res Ther 2020 09 25;22(1):223. Epub 2020 Sep 25.

UPMC, Université Paris 6, Paris, France.

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 patients.

Methods: HCQ levels were measured in serum and whole blood from 573 patients with systemic lupus erythematosus (SLE). The risk factors for active SLE (SLEDAI score > 4) were identified by multiple logistic regression. Serum HCQ levels were measured in 68 additional patients known to be non-adherent, i.e. with whole-blood HCQ < 200 ng/mL.

Results: The mean (± SD) HCQ levels were 469 ± 223 ng/mL in serum and 916 ± 449 ng/mL in whole blood. The mean ratio of serum/whole-blood HCQ levels was 0.53 ± 0.15. In the multivariate analysis, low whole-blood HCQ levels (P = 0.023), but not serum HCQ levels, were independently associated with active SLE. From the mean serum/whole-blood level ratio, a serum HCQ level of 106 ng/mL was extrapolated as the corresponding cut-off to identify non-adherent patients with a sensitivity of 0.87 (95% CI 0.76-0.94) and specificity of 0.89 (95% CI 0.72-0.98). All serum HCQ levels of patients with whole-blood HCQ below the detectable level (< 20 ng/mL) were also undetectable (< 20 ng/mL).

Conclusions: These data suggest that whole blood is better than serum for assessing the pharmacokinetic/pharmacodynamic relation of HCQ. Our results support the use of serum HCQ levels to assess non-adherence when whole blood is unavailable.
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http://dx.doi.org/10.1186/s13075-020-02291-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517694PMC
September 2020

Genetics of digestive efficiency in growing pigs fed a conventional or a high-fibre diet.

J Anim Breed Genet 2021 Mar 20;138(2):246-258. Epub 2020 Sep 20.

GenPhySE, Université de Toulouse, INRAE, ENVT, Castanet Tolosan, France.

The use of diets with increased dietary fibre content (HF) from alternative feedstuffs is a solution to limit the impact of increased feed costs on pig production. This study aimed at determining the impact of an alternative HF diet on pig digestibility and at estimating genetic parameters of this trait. Digestibility coefficients (DC) of energy, organic matter and nitrogen were predicted from faecal samples analysed with near infrared spectrometry for 1,242 samples, and it represented 654 Large White pigs fed a conventional (CO) diet and 588 fed a HF diet. Growth and feed efficiency traits, carcass composition and meat quality traits were recorded. Pigs fed the HF diet had significantly lower DC than pigs fed the CO diet (-4.5 to 6.0 points). The DC were moderately to highly heritable (about 0.26 ± 0.12 and 0.54 ± 0.15 in the CO and the HF diet, respectively). Genetic correlations were favourable with feed conversion ratio, daily feed intake and residual feed intake, but unfavourable with average daily gain (ADG) and carcass yield (CY). To conclude, DC could be an interesting trait to include in future breeding objectives if pigs were fed diet with HF diets, but adverse genetic trends with ADG and CY would have to be taken into account.
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http://dx.doi.org/10.1111/jbg.12506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891433PMC
March 2021

Population Pharmacokinetics of Erlotinib in Patients With Non-small Cell Lung Cancer: Its Application for Individualized Dosing Regimens in Older Patients.

Clin Ther 2020 07 4;42(7):1302-1316. Epub 2020 Jul 4.

Center for Research and Innovation in Clinical Pharmaceutical Sciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Geneva, Switzerland; School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. Electronic address:

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 to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib.

Methods: A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups.

Findings: A total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h. The external validation showed a negligible bias of -4% (95% CI, -7 to -1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure.

Implications: This large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities.
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http://dx.doi.org/10.1016/j.clinthera.2020.05.008DOI Listing
July 2020

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma.

Cancers (Basel) 2020 Apr 9;12(4). Epub 2020 Apr 9.

Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.

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 melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances ( < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC/AUC ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); = 0.023 and 10.61 (2.34-48.15), = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); = 0.032 and HR = 1.23 (1.35-10.39), = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC/AUC deserves more investigation in a larger cohort of MM patients.
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http://dx.doi.org/10.3390/cancers12040931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226106PMC
April 2020

Pharmacogenetic-Whole blood and intracellular pharmacokinetic-Pharmacodynamic (PG-PK2-PD) relationship of tacrolimus in liver transplant recipients.

PLoS One 2020 12;15(3):e0230195. Epub 2020 Mar 12.

Rennes 1 University, Rennes University Hospital, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, Rennes, France.

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 (Predose, and 20 min, 40 min, 1h, 2h, 3h, 4h, 6h, 8h, 12h post drug intake) of twice daily TAC in whole blood and peripheral blood mononuclear cells (PBMC) were collected in 32 liver transplanted patients in the first ten days post transplantation. A non-parametric population pharmacokinetic model was applied to explore TAC pharmacokinetics in blood and PBMC. Concurrently, calcineurin activity was measured in PBMC. Influence of donor and recipient genetic polymorphisms of ABCB1, CYP3A4 and CYP3A5 on TAC exposure was assessed. Recipient ABCB1 polymorphisms 1199G>A could influence TAC whole blood and intracellular exposure (p<0.05). No association was found between CYP3A4 or CYP3A5 genotypes and TAC whole blood or intracellular concentrations. Finally, intra-PBMC calcineurin activity appeared incompletely inhibited by TAC and less than 50% of patients were expected to achieve intracellular IC50 concentration (100 pg/millions of cells) at therapeutic whole blood concentration (i.e.: 4-10 ng/mL). Together, these data suggest that personalized medicine regarding TAC therapy might be optimized by ABCB1 pharmacogenetic biomarkers and by monitoring intracellular concentration whereas the relationship between intracellular TAC exposure and pharmacodynamics biomarkers more specific than calcineurin activity should be further investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230195PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067455PMC
June 2020

Long Term Pharmacological Perturbation of Autophagy in Mice: Are HCQ Injections a Relevant Choice?

Biomedicines 2020 Mar 1;8(3). Epub 2020 Mar 1.

Université Paris Est-Créteil, Faculté de Santé, INSERM U955 Eq. Relaix, Biologie du système neuromusculaire, F-94010 Créteil, France.

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 and unwanted autophagy-independent phenotypes, limiting their applications for studies. To avoid problems encountered with autophagy-null transgenic mice, we investigated the possibility of disturbing autophagy pharmacologically in the long term. Hydroxychloroquine (HCQ) ip injections were done in juvenile and adult C57bl/6j mice, at range doses adapted from the human malaria prophylactic treatment. The impact on autophagy was assessed by western-blotting, and juvenile neurodevelopment and adult behaviours were evaluated for four months. Quite surprisingly, our results showed that HCQ treatment in conditions used in this study neither impacted autophagy in the long term in several tissues and organs nor altered neurodevelopment, adult behaviour and motor capabilities. Therefore, we recommend for future long-term in vivo studies of autophagy, to use genetic mouse models allowing conditional inhibition of selected genes in appropriate lineage cells instead of HCQ treatment, until it could be successfully revisited using higher HCQ doses and/or frequencies with acceptable toxicity.
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http://dx.doi.org/10.3390/biomedicines8030047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148514PMC
March 2020

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study.

Cancers (Basel) 2020 Feb 18;12(2). Epub 2020 Feb 18.

Drug Biology-Toxicology, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.

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 survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of -mutated () NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55-109) vs. 658 days (222-not reached); HR: 4.12 (1.95-8.71), = 0.0002) and OS (HR: 3.99(1.63-9.80), = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17-6.08), = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30-0.80), = 0.004) and OS (HR: 0.39, 95%CI (0.21-0.71), = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.
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http://dx.doi.org/10.3390/cancers12020473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072584PMC
February 2020

Pharmacogenetics and pharmacokinetics modeling of unexpected and extremely severe toxicities after sorafenib intake.

Pharmacogenomics 2020 02;21(3):173-179

Medical Oncology Unit, La Timone University Hospital of Marseille Assistance Publique Hôpitaux de Marseille, Marseille, France.

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 further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 (-rs3832043) and nuclear receptor PXR (-rs3814055-rs2472677 and -rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting , genetic polymorphisms of have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.
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http://dx.doi.org/10.2217/pgs-2019-0127DOI Listing
February 2020

The impact of body composition parameters on severe toxicity of nivolumab.

Eur J Cancer 2020 01 30;124:170-177. Epub 2019 Nov 30.

Department of Medical Oncology, Cochin Hospital, AP-HP 5, CARPEM, CERTIM, Paris, France; Laboratory of Biological Nutrition EA, Pharmacy University, Université Paris Descartes, 4466, Paris, France.

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 parameters influencing nivolumab toxicity, including body composition.

Methods: From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (C) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]).

Results: In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab C at day 14 was 15.4 μg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab C on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab C on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma C at day 14.

Conclusions: Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.
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http://dx.doi.org/10.1016/j.ejca.2019.11.003DOI Listing
January 2020

Is there an Exposure-Response Relationship for Nivolumab in Real-World NSCLC Patients?

Cancers (Basel) 2019 Nov 13;11(11). Epub 2019 Nov 13.

Department of Pharmacokinetics and Pharmacochemisty, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.

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 trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman's rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL ( = 76), 25.6 ± 10.2 µg/mL ( = 64) and 33.4 ± 11.3 µg/mL ( = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02-3.38, -value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78-36.62, -value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46-27.08, -value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.
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http://dx.doi.org/10.3390/cancers11111784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895963PMC
November 2019

Pharmacokinetic/Pharmacodynamic Relationship of Enzalutamide and Its Active Metabolite N-Desmethyl Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients.

Clin Genitourin Cancer 2020 04 13;18(2):155-160. Epub 2019 Jun 13.

Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France; Inserm U1268, CiTCom UMR8038 CNRS, Pharmacy UFR, University of Paris Descartes, PRES sorbonne Paris Cité, Paris, France.

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 metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting.

Patients And Methods: Trough plasma concentration (C) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann-Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma C (ENZA, NDE, and composite).

Results: Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma C of ENZA and NDE were 12.4 ± 3.0 μg/mL and 8.8 ± 2.1 μg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma C. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma C was observed compared with 18 remaining patients (16.1 ± 2.4 μg/mL vs. 11.6 ± 2.6 μg/mL, respectively; P = .027).

Conclusion: The low interindividual variability in ENZA and NDE C and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.
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http://dx.doi.org/10.1016/j.clgc.2019.05.020DOI Listing
April 2020

Therapeutic Drug Monitoring of Targeted Anticancer Protein Kinase Inhibitors in Routine Clinical Use: A Critical Review.

Ther Drug Monit 2020 02;42(1):33-44

Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne.

Background: 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 (PK) variability affecting blood concentrations, fluctuating medication adherence, and constitutional or acquired drug resistance of cancer cells. The appropriate management of oncology patients with PKI treatments thus requires concerted efforts to optimize the utilization of these drug agents, which have probably not yet revealed their full potential.

Methods: An extensive literature review was performed on MEDLINE on the PK, pharmacodynamics, and therapeutic drug monitoring (TDM) of PKIs (up to April 2019).

Results: This review provides the criteria for determining PKIs suitable candidates for TDM (eg, availability of analytical methods, observational PK studies, PK-pharmacodynamics relationship analysis, and randomized controlled studies). It reviews the major characteristics and limitations of PKIs, the expected benefits of TDM for cancer patients receiving them, and the prerequisites for the appropriate utilization of TDM. Finally, it discusses various important practical aspects and pitfalls of TDM for supporting better implementation in the field of cancer treatment.

Conclusions: Adaptation of PKIs dosage regimens at the individual patient level, through a rational TDM approach, could prevent oncology patients from being exposed to ineffective or unnecessarily toxic drug concentrations in the era of personalized medicine.
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http://dx.doi.org/10.1097/FTD.0000000000000699DOI Listing
February 2020

Differential Kinase Activation in Peripheral Blood Mononuclear Cells from Non-Small-Cell Lung Cancer Patients Treated with Nivolumab.

Cancers (Basel) 2019 May 31;11(6). Epub 2019 May 31.

Biologie du médicament-toxicologie, Hôpital Cochin, AP-HP, 75014 Paris, France.

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 (STK) activity in PBMC from non-small-cell lung cancer (NSCLC) patients using a high throughput kinomic profiling method. PamChip microarrays were used to explore the STK kinomic profile in PBMC from 28 NSCLC patients before nivolumab initiation (D0) and on day 14 (D14) of the first administration. Two clusters of patients (A and B) were identified at D0, median overall survival (OS) tended to be longer in cluster A than in B (402 vs. 112.5 days, respectively; p = 0.15). Interestingly, the PD-L1 tumor cell score (p = 0.045), the count of CD8+ cells (p = 0.023) and the total body weight (p = 0.038) were statistically different between the clusters. On D14, clusters C and D were identified. Greater activity of most STK, especially those of the PI3K/Akt signaling pathway, was noticed among cluster C. No significant difference between C and D was observed regarding OS. Considering the small number of patients, results from this preliminary study are not conclusive. However, the 4-fold longer median OS in cluster A paves the way to further investigate, in a larger cohort of NSCLC patients, the benefit of basal STK kinomic profile in PBMC to identify responders to nivolumab therapy.
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http://dx.doi.org/10.3390/cancers11060762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628172PMC
May 2019

Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients.

Clin Ther 2019 05 17;41(5):882-896.e3. Epub 2019 Apr 17.

Département de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; UMR8638 CNRS, UFR Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France. Electronic address:

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 investigating the profile of calcineurin activity (CNA) in the peripheral blood mononuclear cells.

Methods: A conversion from BID immediate-release tacrolimus (IRT) to once-daily PRT based on a one-to-one daily dose was performed at day 7 (D7) and D90 posttransplantation in groups A (n = 12) and B (n = 12), respectively. Extensive PK samplings, including whole-blood tacrolimus (TAC) concentration, and CNA assessments were performed at D14 and D104 in groups A and B, respectively. TAC concentration-time data (N = 221) were analyzed by using nonlinear mixed effects modeling.

Findings: A 2-compartment model with linear elimination and a delayed first-order absorption characterized by 2 transit compartments best described the PK data. Model-predicted dose-normalized (6.0 mg/d) area under the TAC concentration-time curve over the dosing interval in groups A and B was similar (geometric mean, 235.6 ng/mL · h [95% CI, 139.6-598.7] vs 224.6 ng/mL · h [95% CI, 117.6-421.5], respectively; P = 0.94). Area under the CNA versus time curve over the dosing interval did not differ between groups (4897 [3437] and 4079 [1008] pmol/min/10 cells; P = 0.50). In group A, trough CNA at D14 posttransplantation was statistically higher than that measured just before the switch to PRT (ie, D7 posttransplantation) (198 [92] vs 124 [72] pmol/min/10cells, n = 8; P = 0.048); no statistical difference in TAC concentration was observed (P = 0.11). In group B, no statistical difference between D90 and D104 was observed in either trough CNA (149 [78] vs 172 [82] pmol/min/10 cells, n = 6; P = 0.18) or TAC (P = 0.17) concentration. No graft rejection was observed in either of the groups.

Implications: This study suggests that one-to-one dosage conversion to once-daily PRT during the early posttransplantation period could result in significant CNA variations but without causing graft rejection. Further investigations in larger cohorts are warranted to confirm these results. ClinicalTrials.gov identifier: NCT02105155.
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http://dx.doi.org/10.1016/j.clinthera.2019.03.006DOI Listing
May 2019

Pharmacokinetic interaction between mitotane and etoposide in adrenal carcinoma: a pilot study.

Endocr Connect 2018 Dec;7(12):1409-1414

Pharmacokinetics and Pharmacochemistry Unit, Cochin Hospital, Paris Descartes University, AP-HP, Paris, France.

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 chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods Five consecutive ACC patients treated with platinum etoposide (120-150 mg/m2 day 1-2-3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04). Conclusion A drug-drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.
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http://dx.doi.org/10.1530/EC-18-0428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301193PMC
December 2018

[Issues of oral targeted therapies in daily clinical practice: 5th edition of the congress of pharmacology of anticancer drugs].

Bull Cancer 2018 Nov 8;105(11):1102-1109. Epub 2018 Oct 8.

Hôpital Cochin, service d'oncologie médicale, 123, boulevard de Port-Royal, 75014 Paris, France. Electronic address:

Oral targeted therapies are a growing class of medication. After clinical trials conducted on a selected population, these molecules are usually approved at a fixed dose. However, oral tyrosine kinase inhibitors are characterized by a large intra and inter-individual pharmacokinetic variability, and a narrow therapeutic index. Hence, their prescription is hazardous and unsafe in non-selected people from daily clinical practice. The increasing number of available targeted therapies point out new challenges. These challenges should especially concern prescription for out of the ordinary patients, rules for dose adjustment according to factors of frailty. The ultimate goal is to ensure a safe and individualized prescription. Moreover, many of these molecules are metabolized by the CYP3A4, leading to a serious risk of drug interaction. These interactions might involve not only conventional medicine but also alternative and complementary medicines. These latter are more and more common but oncologists often lack experience about them. Finally, the oral route raises the issues of adherence, and the question of its assessment should now become a permanent part of patients care.
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http://dx.doi.org/10.1016/j.bulcan.2018.08.005DOI Listing
November 2018

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters.

Fundam Clin Pharmacol 2019 Feb 14;33(1):113-121. Epub 2018 Oct 14.

Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology, Drug Information Centre, Rennes University Hospital, 2 rue Henri Le Guilloux, 35033, Rennes, France.

Measuring tacrolimus (TAC) concentration in peripheral blood mononuclear cells (PBMCs) 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 PBMC and investigating the contribution of membrane transporters to regulate TAC intracellular concentration as well as the impact on CaN activity. PBMCs were incubated with TAC for 5 min to 4 h and under several experimental conditions: 37 °C (physiological conditions), 4 °C (inhibition of influx and efflux active transport), 37 °C + transporter inhibitors (verapamil, carvedilol, and probenecid and bromosulfophthalein, respectively, inhibitors of P-gp, OAT, and OATP). TAC concentration and CaN activity were measured in PBMC using liquid chromatography coupled with mass spectrometry. TAC intra-PBMC concentration was maximal after 1 h of incubation. Mean TAC PMBC concentrations were significantly lower in samples incubated at 4 °C compared to the 37 °C groups. Addition of verapamil slightly increased TAC accumulation in PBMC while other inhibitors had no effect. A significant correlation was found between TAC intra-PBMC concentration and the level of inhibition of CaN. Using an ex vivo cellular model, these results suggest that P-gp is involved in the drug efflux from PBMC while influx active transporters likely to regulate TAC intra-PBMC disposition remain to be identified. TAC concentration in PBMC is correlated with its pharmacodynamic effect. Then, TAC intra-PBMC concentration appears to be a promising biomarker to refine TAC therapeutic drug monitoring.
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http://dx.doi.org/10.1111/fcp.12412DOI Listing
February 2019

Low-Dose Abiraterone Regimen: Drug Monitoring Might Be the Key.

J Clin Oncol 2018 10 6;36(30):3061-3062. Epub 2018 Sep 6.

Manuela Tiako Meyo, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, and Cancer Research and Personalized Medicine, Paris, France; Jérôme Alexandre and François Goldwasser, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris; Cancer Research and Personalized Medicine; and Cochin Institute, Institut National de la Santé et de la Recherche Médicale U1016, Paris, France; and Benoit Blanchet, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris; Cancer Research and Personalized Medicine; and University of Paris Descartes, Université Sorbonne Paris Cité, Paris, France.

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http://dx.doi.org/10.1200/JCO.2018.79.3174DOI Listing
October 2018

A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients.

Pharmacol Res 2018 10 22;136:56-61. Epub 2018 Aug 22.

Department of Medical Oncology, Hôpital Cochin, AP-HP, Paris, France; University of Paris Descartes, CARPEM, Paris, France; Cochin Institute, INSERM U1016, Paris, France. Electronic address:

Δ-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 mCRPC patients treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day). Plasma trough ABI and Δ4A concentrations were monthly assayed using liquid chromatography during the first 3 months of treatment. ABI and Δ4A C were defined as the mean of trough concentrations measured for each patient. Predictive factors regarding progression-free survival (PFS) and overall survival (OS) were explored using univariate Cox model. Mean plasma ABI and Δ4A C were 12.6 ± 6.8 ng/mL and 1.6 ± 1.3 ng/mL, respectively. The mean metabolic ratio Δ4A/ABI was of 0.18 ± 0.25. In regard with in vitro pharmacodynamic data, effective plasma concentrations for ABI and Δ4A were reached in 30 patients (83.3%) and only 2 patients (5.6%), respectively. Higher Δ4A C was associated with shorter OS (Hazard ratio, HR 1.54; CI95% 1.06-2.22; p = 0.022) but not with PFS. The HR associated with the metabolic Δ4A/ABI ratio for PFS and OS were 7.80 (CI 95% 1.63-37.38; p = 0.010) and 12.52 (CI 95% 1.95-80.47, p = 0.0078), respectively. The present study shows Δ4A is unlikely to have meaningful contribution to pharmacodynamic activity of ABI in mCPRC, rather that higher plasma Δ4A concentration is associated with worse clinical outcomes. A high Δ4A/ABI metabolic ratio could help to identify mCRPC patients with poorer survival.
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http://dx.doi.org/10.1016/j.phrs.2018.08.016DOI Listing
October 2018

Pharmacokinetic variability of anticoagulants in patients with cancer-associated thrombosis: Clinical consequences.

Crit Rev Oncol Hematol 2018 Sep 9;129:102-112. Epub 2018 Jul 9.

Centre d'Étude et de Recours aux Inhibiteurs de l'Angiogénèse, GH Cochin Port-Royal, HUPC, AP-HP, Paris Descartes, 75014 Paris, France; UF de Pharmacocinétique et Pharmacochimie, Hôpital Cochin, AP-HP, Paris Descartes, CARPEM, 75014 Paris, France; UMR8638 CNRS, UFR de Pharmacie, Université Paris Descartes, PRES Sorbonne Paris Cité, France. Electronic address:

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-associated thrombosis (CAT) in real life are scarce since patients with cancer presenting with significant comorbidities tend to be excluded from large trials. This review is mostly based on case-reports and pharmacokinetics in an attempt to provide oncologists, with relevant orientation based on our best knowledge to date. Overall, low-molecular-weight heparins (LMWH) are the preferred option for the long-term prophylaxis and treatment of CAT as their benefit-risk was shown superior to vitamin K antagonists (VKA). Direct oral anticoagulants (DOAC) may represent an alternative to LMWH provided that a favorable benefit-risk in patients with CAT is evidenced in the future. We recommend a systematic risk-assessment including body composition, multiple medication, and renal function. Moreover a systematic and early discussion between pharmacist and oncologist should optimize the benefit-risk ratio for each patient.
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http://dx.doi.org/10.1016/j.critrevonc.2018.06.015DOI Listing
September 2018

Clinical Pharmacokinetics and Pharmacodynamics of Dabrafenib.

Clin Pharmacokinet 2019 04;58(4):451-467

UMR8638 CNRS, Faculty of Pharmacy, University Paris Descartes, PRES Sorbonne Paris Cité, Paris, France.

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 BRAF mutation. The recommended dose of dabrafenib is 150 mg twice daily (bid) under fasted conditions. After single oral administration of the recommended dose, the absolute oral bioavailability (F) of dabrafenib is 95%. Dabrafenib shows a time-dependent increase in apparent clearance (CL/F) following multiple doses, which is likely due to induction of its own metabolism through cytochrome P450 (CYP) 3A4. Therefore, steady state is reached only after 14 days of daily dose administration. Moreover, the extent of this auto-induction process is dependent on the dose, which explains why dabrafenib systemic exposure at steady state increases less than dose proportionally over the dose range of 75-300 mg bid. The main elimination route of dabrafenib is the oxidative metabolism via CYP3A4/2C8 and biliary excretion. Among the three major metabolites identified, hydroxy-dabrafenib appears to contribute to the pharmacological activity. Age, sex and body weight did not have any clinically significant influence on plasma exposure to dabrafenib. No dose adjustment is needed for patients with mild renal or hepatic impairment, whereas the impacts of severe impairment on dabrafenib pharmacokinetics remain unknown. Considering that dabrafenib is a substrate of CYP3A4/2C8 and is a CYP3A4/2B6/2C inducer, drug-drug interactions are expected with dabrafenib. The relationship between clinical outcomes and plasma exposure to dabrafenib and hydroxy-dabrafenib should be investigated more deeply.
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http://dx.doi.org/10.1007/s40262-018-0703-0DOI Listing
April 2019

Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the EGFR inhibitors afatinib, erlotinib and osimertinib, the ALK inhibitor crizotinib and the VEGFR inhibitor nintedanib in human plasma from non-small cell lung cancer patients.

J Pharm Biomed Anal 2018 Sep 1;158:174-183. Epub 2018 Jun 1.

Pharmacokinetics and Pharmacochemistry Unit, CERIA, Cochin Hospital, APHP, Paris Descartes, CARPEM, 75014, Paris, France; UMR8638 CNRS, Pharmacy UFR, University of Paris Descartes, PRES sorbonne Paris Cité, France.

A new method for the quantitative analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) of five tyrosine kinase inhibitors (afatinib, crizotinib, osimertinib, erlotinib and nintedanib) used in the treatment of non-small cell lung cancer (NSCLC) was developed and validated in human plasma. Separation was performed on an Accucore C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1% (v/v) formic acid (A) and acetonitrile containing 0.1% (v/v) formic acid (B) at a flow rate of 500 μL/min. The analytes were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with heated electrospray interface. After addition of three isotopically labeled internal standards, plasma pretreatment consisted in a simple protein precipitation. This method presented satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-assay coefficient of variation from 2.6% to 10.6%), accuracy (from 96.1% to 108.5%), recovery and matrix effects. The lower limit of quantification and the linearity of these five tyrosine kinases inhibitors are suitable with the expected concentrations in clinical practice. This new bioanalytical method can be used in daily clinical practice for therapeutic drug monitoring of these tyrosine kinase inhibitors in NSCLC patients.
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http://dx.doi.org/10.1016/j.jpba.2018.05.052DOI Listing
September 2018

Drug monitoring of sunitinib in patients with advanced solid tumors: a monocentric observational French study.

Fundam Clin Pharmacol 2018 Feb 10;32(1):98-107. Epub 2017 Nov 10.

Department of Medical Oncology, Cochin Hospital, AP-HP, 27 rue du Faubourg Saint Jacques, 75014, Paris, France.

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 treated with sunitinib were prospectively monitored between days 21 and 28 of the first cycle, then monthly until disease progression. At each consultation, the composite AUC (sunitinib + active metabolite SU12662) was assayed. The decisions taken during each consultation were matched with AUC and compared to the decisional algorithm based on TDM. A total of 105 cancer patients and 288 consultations were matched with the closest AUC measurement. The majority (60%) of the patients had metastatic renal clear-cell carcinoma (mRCC). Fifty-five (52%) patients experienced grade 3-4 toxicity. Multivariate analysis identified composite AUC as a parameter independently associated with grade 3-4 toxicity (P < 0.0001). Using the ROC curve, the threshold value of composite AUC predicting grade ≥3 toxicity was 2150 ng/mL/h (CI 95%, 0.6-0.79%; P < 0.0001). At disease progression in patients with mRCC, AUC tended to be lower than the one assayed during the first cycle (1678 vs. 2004 ng/mL/h, respectively, P = 0.072). TDM could have changed the medical decision for sunitinib dosing in 30% of patients at the first cycle of treatment, and in 46% of the patients over the whole treatment course. TDM is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure at the time of disease progression.
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http://dx.doi.org/10.1111/fcp.12327DOI Listing
February 2018