ABSTRACT In our institution, therapeutic drug monitoring of daptomycin is performed routinely and cases of high trough concentrations have been observed in patients without known risk factors. The aim of this study was to identify risk factors of daptomycin overexposure. We performed a case-control study of daptomycin overexposure in patients who received daptomycin between 2013 and 2021. Cases and controls were defined as patients with trough concentration (Cmin) ≥60 mg/L and Cmin <60 mg/L, respectively. Univariate and multivariate analyses were performed with logistic regression models. Retained variables were further analyzed by subgroup analysis and comparison of the pharmacokinetic parameters of daptomycin. We analyzed data from 78 and 26 patients in the control and case groups, respectively. The male-to-female ratio was 1.5. The median (interquartile range) of age, body weight, and creatinine clearance was 66.5 (55–77) years, 77 (65–96) kg, and 98.5 (53–124) mL/min, respectively. Increasing body mass index (BMI) and co-administration of irbesartan were identified as risk factors of daptomycin overexposure with odds ratio (OR) (95% confidence interval [CI]) of 2.9 [1.4–6.2], and 6.1 [1.1–40.8], respectively, whereas increasing creatinine clearance was associated with decreasing risk, with OR of 0.16 [0.05–0.35]. The influence of BMI was attributed to the non-linear relationship between body weight and daptomycin PK parameters and the use of weight-based dosing in patients with high BMI. In addition to renal impairment, high BMI and irbesartan co-administration may be associated with an augmented risk of daptomycin overexposure. Dosing based on actual body weight should be avoided in obese patients.

Given its good tolerance and broad-spectrum, isavuconazole is increasingly used off-label as an empirical therapy of invasive fungal infections. We retrospectively reviewed isavuconazole empirical treatment during a 12-month period in four hospitals. During isavuconazole treatment (n=27), none of the patients had a mycological evidence for fungal infection, but 19% (5/27) developed liver test abnormalities without leading to isavuconazole discontinuation. Isavuconazole could be considered as an off-label empirical therapy only if patients cannot receive caspofungin or liposomal amphotericin B.

BACKGROUND:Posaconazole (PCZ) is recommended for antifungal prophylaxis in neutropenic patients with acute myeloid leukemia (AML). Although the delayed-release (DR) tablet of PCZ has better bioavailability than the oral suspension, the serum target trough concentrations of PCZ are not achieved in all patients. Because the metabolism of PCZ is mainly mediated by uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), we investigated whether UGT1A4 polymorphisms affect PCZ exposure. METHODS:This single-center prospective cohort study included 88 adult patients with AML undergoing myelosuppressive chemotherapy and receiving PCZ prophylaxis with DR tablets. PCZ and PCZ-glucuronide concentrations were measured on days 3, 7, 14, and 21 after chemotherapy initiation using liquid chromatography-tandem mass spectrometry. The patients were genotyped for UGT1A4 polymorphisms using high-throughput sequencing. Logistic regression tested the association between suboptimal PCZ concentrations defined as median PCZ concentrations below 0.5 mg/L during the prophylaxis course and the 2 common UGT1A4 polymorphisms: UGT1A4 (c.70C>A) and UGT1A4 (c.142T>G) (referred to as UGT1A4*2 and *3 , respectively). RESULTS:Suboptimal PCZ concentrations were common despite treatment with PCZ DR tablets in induction chemotherapy: 13/88 (15%) and consolidation chemotherapy: 6/28 (21%). An increased risk of suboptimal PCZ concentrations was significantly associated with younger age ( P = 0.029), male sex ( P = 0.034), and presence of the UGT1A4*3 haplotype ( P = 0.031). In addition, patients with the UGT1A4*3 haplotype tended to have higher metabolite-to-parent drug ratios than noncarriers ( P = 0.069). CONCLUSIONS:The UGT1A4*3 polymorphism independently contributed to the risk of suboptimal PCZ concentrations in patients with AML taking DR tablets.

BACKGROUND:Isavuconazole is a recent broad-spectrum triazole indicated for the treatment of invasive aspergillosis and mucormycosis when amphotericin B is inappropriate. However, limited information exists on its clinical use. OBJECTIVE:We set up a retrospective multicentre study to describe the clinical practice of isavuconazole including indications, exposure, and hepatic safety. METHODS:From January 2021 to June 2023, all patients who received isavuconazole and had at least one therapeutic drug monitoring (TDM) measurement, were included. To identify independent predictors of isavuconazole trough concentrations (Cmin), linear regression analyses were performed. Causal relationship between the occurrence of liver injury and isavuconazole was also analysed. RESULTS:Most of the included patients (n = 102) were admitted into haematology units (41.1% [n = 42]) or intensive care units (ICU) (30.4% [n = 31]). Aspergillosis (47.0% [n = 48]), mucormycosis (25.6% [n = 26]), and off-label empirical treatments (18.6% [n = 19]), were the three most common indications. About half of the patients (46.1% [n = 47]) had an optimal exposure, while 42.2% (n = 43) were underexposed, and 11.7% (n = 12) were overexposed. Albumin level on the day of TDM was a significant factor associated with an increase in isavuconazole Cmin (p = 0.010). Among the 11 patients who had liver test abnormalities, isavuconazole was discontinued in six (n = 6) patients and liver injury was attributable to isavuconazole in two (n = 2) patients. CONCLUSIONS:This multicentre analysis highlighted the common use of isavuconazole as an off-label indication, as well as the frequent underexposure of patients to isavuconazole. Albumin on the day of TDM appeared to be an important factor driving isavuconazole exposure, especially in ICU patients.

Limited information is available on the pharmacokinetics of rifampicin (RIF) along with that of its active metabolite, 25-deacetylrifampicin (25-dRIF). This study aimed to analyse the pharmacokinetic data of RIF and 25-dRIF collected in adult patients treated for tuberculosis. In adult patients receiving 10 mg/kg of RIF as part of a standard regimen for drug-susceptible pulmonary tuberculosis enrolled in the Opti-4TB study, plasma RIF and 25-dRIF concentrations were measured at various occasions. The RIF and 25-dRIF concentrations were modelled simultaneously by using a population approach. The area under the concentration–time curves of RIF and 25-dRIF were estimated on each occasion of therapeutic drug monitoring. Optimal RIF exposure, defined as an area under the concentration–time curve over 24 hours/minimum inhibitory concentration > 435, was assessed. Concentration data (247 and 243 concentrations of RIF and 25-dRIF, respectively) were obtained in 35 patients with tuberculosis (10 women, 25 men). Mycobacterium tuberculosis minimum inhibitory concentration ranged from 0.06 to 0.5 mg/L (median = 0.25 mg/L). The final model was a two-compartment model including RIF metabolism into 25-dRIF and auto-induction. Exposure to 25-dRIF was low, with a mean area under the concentration–time curve over 24 h ratio of 25-dRIF/RIF of 14 ± 6

Large pharmacokinetic (PK) variability of fluconazole has been reported in critically ill patients, but the implications for fluconazole dosing remain unclear. The objectives of this study were to evaluate the population PK of fluconazole and identify appropriate dosage regimens by simulations. This was a retrospective analysis of fluconazole PK data from patients hospitalized in critical care and infectious disease departments. Both parametric and nonparametric population approaches were used. Various loading and maintenance fluconazole doses were evaluated by simulations, with computation of the probabilities of PK/pharmacodynamic (PD) target attainment (PTA) and cumulative fractions of response (CFR) based on international and local minimum inhibitory concentration (MIC) distributions of Candida sp. Data from 36 critically ill patients and 16 non-critically ill patients were available for model building (n = 202 concentrations). The final model adequately described the data, including the external data set (13 patients). After 24 h of therapy, 65% and 74% of patients had trough and area under the concentration-time curve values below the usual targets. Standard dosages were associated with low PTA for MIC >1 mg/L at 24 h. Higher loading doses administered two times daily improved PTA. CFR were >90% for C. albicans with standard dosages, while they were very low for C. glabrata, even with high dosages. Candida species and associated MIC distributions strongly influence fluconazole dosage requirements. Higher loading doses may be necessary for the achievement of PK/PD targets up to MIC breakpoints. The use of fluconazole for invasive C. glabrata infection should be discouraged because of poor PK/PD target attainment.

Journal Article Corrected proof Reply to Tannous et al. Get access Romain Garreau, Romain Garreau Groupement Hospitalier Nord, Service de Pharmacie, Hospices Civils de Lyon, Lyon, FranceLBBE—Laboratoire de Biométrie et Biologie Evolutive, CNRS, UMR 5558, Université Lyon 1, Villeurbanne, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Truong-Thanh Pham, Truong-Thanh Pham Division of Infectious Diseases, Geneva University Hospitals, Geneva, SwitzerlandGroupement Hospitalier Nord, Hôpital de la Croix-Rousse, Service des Maladies Infectieuses et Tropicales, Centre de Référence pour la prise en charge des Infections Ostéo-Articulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Laurent Bourguignon, Laurent Bourguignon Groupement Hospitalier Nord, Service de Pharmacie, Hospices Civils de Lyon, Lyon, FranceLBBE—Laboratoire de Biométrie et Biologie Evolutive, CNRS, UMR 5558, Université Lyon 1, Villeurbanne, FranceISPB, Facultés de Médecine et de Pharmacie de Lyon, University of Lyon, Université Lyon 1, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Aurélien Millet, Aurélien Millet Groupement Hospitalier Sud, Service de Biochimie et Biologie Moléculaire, UM Pharmacologie - Toxicologie, Hospices Civils de Lyon, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar François Parant, François Parant Groupement Hospitalier Sud, Service de Biochimie et Biologie Moléculaire, UM Pharmacologie - Toxicologie, Hospices Civils de Lyon, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar David Bussy, David Bussy Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, Service des Maladies Infectieuses et Tropicales, Centre de Référence pour la prise en charge des Infections Ostéo-Articulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Marine Desevre, Marine Desevre Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, Service des Maladies Infectieuses et Tropicales, Centre de Référence pour la prise en charge des Infections Ostéo-Articulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Victor Franchi, Victor Franchi Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, Service des Maladies Infectieuses et Tropicales, Centre de Référence pour la prise en charge des Infections Ostéo-Articulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Tristan Ferry, Tristan Ferry Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, Service des Maladies Infectieuses et Tropicales, Centre de Référence pour la prise en charge des Infections Ostéo-Articulaires complexes (CRIOAc Lyon), Hospices Civils de Lyon, Lyon, FranceISPB, Facultés de Médecine et de Pharmacie de Lyon, University of Lyon, Université Lyon 1, Lyon, FranceCIRI—Centre International de Recherche en Infectiologie, Inserm, U1111, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université́ Claude Bernard Lyon 1, University of Lyon Lyon, France Search for other works by this author on: Oxford Academic PubMed Google Scholar Sylvain Goutelle Sylvain Goutelle Groupement Hospitalier Nord, Service de Pharmacie, Hospices Civils de Lyon, Lyon, FranceLBBE—Laboratoire de Biométrie et Biologie Evolutive, CNRS, UMR 5558, Université Lyon 1, Villeurbanne, FranceISPB, Facultés de Médecine et de Pharmacie de Lyon, University of Lyon, Université Lyon 1, Lyon, France Correspondence: S. Goutelle, Groupement Hospitalier Nord, Hôpital de la Croix-Rousse, Service de pharmacie, Hospices Civils de Lyon, 104 grande rue de la Croix-Rousse, 69004 Lyon, France (sylvain.goutelle@chu-lyon.fr). https://orcid.org/0000-0002-1853-2932 Search for other works by this author on: Oxford Academic PubMed Google Scholar Clinical Infectious Diseases, ciae018, https://doi.org/10.1093/cid/ciae018 Published: 17 January 2024 Article history Received: 10 January 2024 Editorial decision: 12 January 2024 Published: 17 January 2024 Corrected and typeset: 07 February 2024

BACKGROUND:High-dose daptomycin is increasingly used in patients with bone and joint infection (BJI). This raises concerns about a higher risk of adverse events (AEs), including daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity. We aimed to examine pharmacokinetic and other potential determinants of DIEP and myotoxicity in patients with BJI receiving daptomycin. METHODS:All patients receiving daptomycin for BJI were identified in a prospective cohort study. Cases were matched at a 1:3 ratio, with controls randomly selected from the same cohort. Bayesian estimation of the daptomycin daily area under the concentration-time curve over 24 hours (AUC24h) was performed with the Monolix software based on therapeutic drug monitoring (TDM) data. Demographic and biological data were also collected. Risk factors of AEs were analyzed using Cox proportional hazards model. RESULTS:From 1130 patients followed over 7 years, 9 with DIEP, 26 with myotoxicity, and 106 controls were included in the final analysis. Daptomycin AUC24h, C-reactive protein, and serum protein levels were associated with the risk of AEs. The adjusted hazard ratio of DIEP or myotoxicity was 3.1 (95% confidence interval [CI], 1.48-6.5; P < .001) for daptomycin AUC24h > 939 mg/h/L, 9.8 (95% CI, 3.94-24.5; P < .001) for C-reactive protein > 21.6 mg/L, and 2.4 (95% CI, 1.02-5.65; P = .04) for serum protein <72 g/L. CONCLUSIONS:We identified common determinants of DIEP and myotoxicity in patients with BJI. Because the risk of AEs was associated with daptomycin exposure, daptomycin TDM and model-informed precision dosing may help optimize the efficacy and safety of daptomycin treatment in this setting. A target AUC24h range of 666 to 939 mg/h/L is suggested.

Purpose: Increasing evidence supports daptomycin therapeutic drug monitoring. The author's reference center used to perform therapeutic drug monitoring in patients who receive high-dose daptomycin for bone and joint infections, with a three-sample strategy to estimate the daptomycin daily area under the concentration–time curve (AUC). The objective of this study was to evaluate simpler strategies based on only 2 or 1 sample(s). Methods: The authors used the BestDose software to estimate the daptomycin AUC after Bayesian posterior estimation of individual pharmacokinetic (PK) parameters at steady state. The reference AUC (AUCfull) was based on 3 samples obtained predose (T0) and approximately 1 hour (T1) and 6 hours (T6) after the start of a 30-minute infusion of IV daptomycin. It was compared with the AUC based on all possible 2-sample and 1-sample strategies. Bias, imprecision, regression, and Bland–Altman plots were used to assess the performance of the alternative strategies. Results: Data from 77 patients were analyzed. The mean AUCfull value was 936 ± 373 mg·h/L. The best 2-sample strategy was T0 + T6, with a mean prediction bias of 0.13 mg·h/L and absolute imprecision of 3%. The T0 + T1 strategy also performed well with a mean bias of −10 mg·h/L and imprecision of 3%. The best 1-sample strategy was the T6 sample only with a bias of 2.19 mg·h/L and imprecision of 6%. Conclusions: Bayesian estimation of daptomycin AUC based on a two-sample strategy was associated with negligible bias and imprecision compared with the author's usual three-sample strategy. The trough and peak strategy may shorten and simplify patient visits and reduce assay labor and costs.

Abstract Background: Malaria still kills young children in rural endemic areas because early treatment is not available. Thus, the World Health Organization recommends the administration of artesunate suppositories as pre-referral treatment before transportation to the hospital in case of severe symptoms with an unavailable parenteral and oral treatment. However, negative cultural perception of the rectal route, and limited access to artesunate suppositories, could limit the use of artesunate suppositories. There is therefore a need for an alternative route for malaria pre-referral treatment. The aim of this study was to assess the potential of intranasal route for malaria pre-referral treatment.Methods: The permeability of artesunate through human nasal mucosa was tested in vitro. The Transepithelial Electrical Resistance (TEER) of the nasal mucosa was followed during the permeation tests. Beside, regional deposition of artesunate powder was assessed with a unidose drug delivery device in each nostril of a nasal cast. Artesunate quantification was performed using Liquid Chromatography coupled to tandem Mass Spectrometry. Results: The experimental model of human nasal mucosa was successfully implemented. Using this model, artesunate powder showed a much better passage rate through human nasal mucosa than solution (26.8 ± 6.6% versus 2.1 ± 0.3%). More than half (62.3%) of the artesunate dose sprayed in the nostrils of the nasal cast was recovered in the olfactory areas (44.7 ± 8.6%) and turbinates (17.6 ± 3.3%) allowing nose-to-brain and systemic drug diffusion, respectively.Conclusion: Artesunate powder showed a good permeation efficiency on human nasal mucosa. Moreover it can be efficiently sprayed in the nostrils using unidose device to reach the olfactory area leading to a fast nose-to-brain delivery as well as a systemic effect. Taken together, those results are part of the proof-of-concept for the use of intranasal artesunate as a malaria pre-referral treatment.

The results of this communication show that ovine growth hormone (oGH) contains organically-bound phosphorous. The phosphorous content of growth hormone, lot S-11, is 1:3 (mol/mol) and that of lot S-12 is 1:6 (mol/mol). Results of 31P NMR studies suggest that the phosphorous exists in two chemical forms: as a monophosphoryl ester and as a phosphodiester. Evidence is provided which demonstrates that growth hormone can be phosphorylated in vitro with the catalytic subunit of protein kinase.

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 TMDD phenomenon. To help lifting these issues, we have developed and cross-validated a multiplex LC-MS/MS method allowing to assay simultaneously up to 8 mAbs in plasma, including several immune checkpoint inhibitors (i.e., atezolizumab, bevacizumab, cetuximab, ipilimumab, nivolumab, pembrolizumab, rituximab, trastuzumab). Using a ready-to-use kit (mAbXmise), the method proved to be simple and rapid - covering a concentration range of 2-100 µg/ml, in line with plasma concentrations usually expected with mAbs. Inter and intra-assay precision were both <15% and accuracy was comprised between 90.1 and 111.1%, thus meeting the requirements of current EMA guidelines for validating bioanalytical methods. Cross-validation using reference LC-MS/MS or ELISA methods was performed on 7 mAbs (excluding atezolizumab since no reference method was available) with a satisfactory mean absolute bias of 10.6% (3.0-19.9%). This LC-MS/MS method was next used as part of the Cetuximax trial (NCT-04218136), an open, non-randomized, single arm, multicentric study aiming at determining the PK/PD relationships of Cetuximab in Head-and-Neck cancer patients with monitoring of both Cmax and Cmin levels. Patients are all treated with the 250 mg/m² QW schedule. Previous works have suggested that Cetuximab trough levels < 34 µg/ml were associated with higher risk for treatment failure in Head-and-Neck patients. Patients were repeatedly sampled in a longitudinal fashion at their Cmax plus trough levels and individual PK parameters were derived using a pop-PK approach. Preliminary results on 90 samples collected from the first 25 out of the 110 patients to be included have confirmed the marked inter-individual variability in Cetuximab exposure (i.e., >56% on trough levels and >55% on Cmax values). Mean Cetuximab trough level was 54 ± 30 µg/ml (range: 12-104 µg/ml) and mean Cmax value was 211 ± 116 µg/ml (range: 75-418 µg/ml), with several individuals (8 out of 25, i.e., 32%) showing plasma exposure below the expected trough levels associated with efficacy. Although preliminary, our data confirm that PK variability is massive with mAbs. This observation suggests that Therapeutic Drug Monitoring, using appropriate LC-MS/MS method, could help appraising interpatient variability at bedside and detecting individuals with exposure levels out of the range usually observed. Citation Format: Clemence Marin, Nihel Khoudour, Aurélien Millet, Dorothée Lebert, Pauline Bros, Fabienne Thomas, David Ternant, Jerôme Guitton, Mourad Hamimed, Benoit Blanchet, Sebastien Salas, Joseph Ciccolini. A multiplex LC-MS/MS method for assaying mAbs in oncology: Application to the CETUXIMAX GPCO-Unicancer trial on cetuximab pharmacokinetics in head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1144.

Dans le contexte actuel de démocratisation de la consommation de CBD comme drogue récréative et de son expérimentation dans un cadre médical (cannabis thérapeutique), cette étude vise à : – déterminer si le CBD et/ou ses métabolites (7-COOH-CBD et 7-OH-CBD) interfèrent avec la méthode utilisée en routine par le laboratoire Eurofins Biomnis pour le dosage dans le plasma des cannabinoïdes comprenant le delta-9-tétrahydrocannabinol (THC), l'acide 11-nor-9-carboxy-delta-9-tétrahydrocannabinol (THC-COOH) et le 11-hydroxy-delta-9-tétrahydrocannabinol (11-OH-THC). Intérêt de vérifier la spécificité analytique car la méthode LC-MS/MS intervient en confirmation des tests de dépistage salivaires et urinaires (spécificité variable selon le fournisseur) dans un contexte médical (addictologie) et surtout réglementaire (suivi de suspension de permis de conduire). À noter l'absence de données bibliographiques concernant le dosage du CBD, du THC et de leurs métabolites dans le sang à l'aide d'une méthode similaire à celle utilisée ; – évaluer la fréquence de prise de CBD au sein de notre population de patients, en sachant que notre laboratoire réalise chaque mois plus de 900 dosages de cannabinoïdes dans le sang ; – contribuer à mettre au point le dosage qualitatif et quantitatif du CBD dans le plasma pour répondre à une possible recrudescence des demandes dans les années à venir. Chromatographie en phase liquide couplée à la spectrométrie de masse en tandem (LC-MS/MS). Chaîne UPLC/MS Waters avec spectromètre de masse XEVO TQD. Échantillons testés : plasmas fluorure de sodium. Solutions commerciales pour l'étalonnage (Cerilliant) : THC, THC-COOH, 11-OH-THC, THC-D3, THC-COOH-D3, 11-OH-THC-D3, CBD, 7-COOH-CBD, 7-OH-CBD, CBD-C3, 7-COOH-CBD-D3, 7-OH-CBD-D3. Après ajout des standards internes deutérés, déprotéinisation des plasmas par une solution d'acétonitrile, purification sur plaque Waters μElution PRIME HLB puis injection de l'extrait sur colonne Acquity UPLC BEH 1,7 μm avec un gradient de phase mobile eau-acide formique 0,1 %/acétonitrile-acide formique 0,1 %. Essais réalisés : – comparaison des différents étalons de référence et de leurs positions et temps de rétention ; – évaluation qualitative et quantitative d'échantillons de patients (consommation THC isolé, CBD isolé et mixte THC + CBD) et comparaison interlaboratoires avec le LBMMS du CHU de Lyon ; – relevé statistique de présence de CBD sur les séries analysées en routine pour confirmation de cannabis. (1) Les temps de rétention du CBD et de ses métabolites sont significativement inférieurs à ceux du THC et de ses métabolites. (2) Les concentrations en CBD sont comparables entre le laboratoire Eurofins Biomnis et le LBMMS du CHU de Lyon. (3) Mise en évidence de CBD dans environ 2/3 des échantillons de patients testés en routine. (1) Les tests réalisés démontrent l'absence d'interférence du CBD et de ses métabolites (7-COOH-CBD et 7-OH-CBD) sur le dosage dans le plasma du THC et de ses métabolites (THC-COOH et 11-OH-THC) : les temps de rétention des différentes molécules sont bien distincts sur le chromatogramme. Ainsi, l'épaulement du pic THC-COOH parfois constaté en routine chez les consommateurs de CBD ne correspond ni au CBD, ni à l'un de ses métabolites (objectif à venir : optimiser les paramètres chromatographiques de notre méthode afin de ne plus être soumis à cette interférence vraisemblablement liée à d'autres substances contenues dans les spécialités de CBD commercialisées). (2) On constate une proportion de plus en plus importante d'échantillons contenant du CBD dans les séries analysées en routine (consommation en augmentation). (3) Cette étude permet d'envisager le dosage du CBD dans le plasma : son identification est possible sans dégrader les performances analytiques de la méthode LC-MS/MS.

Canakinumab is a fully-human monoclonal immunoglobulin gamma 1 kappa. This interleukin-1β blocker is used for the treatment of autoinflammatory diseases. Various studies have demonstrated the value of therapeutic drug monitoring of monoclonal antibodies in the management of inflammatory diseases. The purpose of this study was to develop a method to quantify canakinumab plasmatic concentration using liquid chromatography-high-resolution (Orbitrap®) mass spectrometry. The quantification was based on a bottom-up approach with the analysis of one surrogate peptide after an immunopurification of IgG followed by tryptic proteolysis. Rituximab and cetuximab, both IgG1, were tested as internal standards. Chromatographic separation was performed on a bioZenTM Peptide PS-C18 column. Mass detection was conducted in positive ionization mode with Parallel Reaction Monitoring at a resolution of 70,000. The method was fully validated in terms of linearity, sensitivity, selectivity, accuracy and matrix effect. Standards ranged from 2.5 to 75 µg/mL. Intra- and inter-day coefficients of variation ranged from 3.7 to 14.7 %, and accuracy from 97.4 to 104.1 %. This method allowed the determination of canakinumab plasmatic concentrations from eight treated patients. This method is efficient and suitable for routine use in therapeutic drug monitoring or pharmacokinetic studies.

Dear Editor, IL-1 inhibitors are mainly used to treat systemic autoinflammatory disorders (SAIDs). Most of these diseases are genetically determined and affect young individuals. For most SAIDs, lifelong treatment is required and many women of reproductive age will not be able to discontinue treatment before conception, during pregnancy or while breastfeeding [1–3]. As with many other DMARDs, there is a lack of available data regarding the use of IL-1 blockers during pregnancy and post-partum [4, 5]. Data mainly arise from case reports or case series, leaving the clinician at a loss when the patient expresses a desire for pregnancy [6–9]. Currently the three available IL-1 inhibitors are anakinra, canakinumab and rilonacept (not marketed in all countries). Canakinumab is a human anti-IL-1β monoclonal antibody, indicated for cryopyrin-associated periodic syndrome (CAPS), TNF receptor–associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), FMF, adult-onset Still's disease...

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 13C6-15N4 and Lysine 13C6-15N2) 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.

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.

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 using a ready-to-use kit to simultaneously assay 7 mAbs (i.e., bevacizumab, cetuximab, ipilimumab, nivolumab, pembrolizumab, rituximab and trastuzumab) in plasma. This method was next cross-validated with respective reference methods (ELISA or LC–MS/MS). Methods: The mAbXmise kit was used for mAb extraction and full-length stable-isotope-labeled antibodies as internal standards. The LC–MS/MS method was fully validated following current EMA guidelines. Each cross validation between reference methods and ours included 16–28 plasma samples from cancer patients. Results: The method was linear from 2 to 100 µg/mL for all mAbs. Inter- and intra-assay precision was <14.6% and accuracy was 90.1–111.1%. The mean absolute bias of measured concentrations between multiplex and reference methods was 10.6% (range 3.0–19.9%). Conclusions: We developed and cross-validated a simple, accurate and precise method that allows the assay of up to 7 mAbs. Furthermore, the present method is the first to offer a simultaneous quantification of three immune checkpoint inhibitors likely to be associated in patients.

Article Potential interference of hydroxychloroquine-glucuronide metabolite on therapeutic drug monitoring of hydroxychloroquine using a mass spectrometry detector was published on July 1, 2020 in the journal Clinical Chemistry and Laboratory Medicine (CCLM) (volume 58, issue 7).