Laurent Arthur Decosterd

Macozinone (MCZ, PBTZ169) is a potent clinical-stage benzothiazinone antitubercular agent that covalently inhibits the essential mycobacterial flavoenzyme DprE1. In some mammals, MCZ undergoes reductive dearomatization to H ₂ MCZ, a Hydride Meisenheimer Complex, identified as the major circulating metabolite in humans. We demonstrate for the first time that the NADPH-dependent human prostaglandin reductases PTGR1 and PTGR2 catalyze MCZ dearomatization into H ₂ MCZ, resulting in loss of antimycobacterial activity. This reaction represents a heretofore undescribed host-mediated metabolic inactivation pathway for a therapeutic agent. Although H ₂ MCZ may constitute a transient reactive intermediate, ex vivo and cellular data indicate that it does not contribute to antimycobacterial activity in vivo. Pharmacological inhibition of PTGR1 and PTGR2 using diclofenac, indomethacin, dicumarol, or the selective inhibitor PTGR2-IN-1 suppresses H ₂ MCZ formation and partially restores MCZ antimycobacterial activity in vitro. Together, these findings uncover a previously unrecognized noncanonical enzymatic mechanism of drug metabolism involving dearomatization in humans. Targeting prostaglandin reductases may represent a strategy to enhance benzothiazinone exposure and efficacy.

Ruxolitinib pharmacokinetics (PK) has been characterized in clinical trials but remains poorly documented in real‐world practice. This project aimed to investigate ruxolitinib PK in routine clinical practice, identify factors driving its variability, and explore exposure–response relationships to assess the potential role of therapeutic drug monitoring. In total, 221 steady‐state ruxolitinib concentrations from 77 adult patients enrolled across several centers in Switzerland were analyzed. Demographic and clinical data were recorded at each visit. Population pharmacokinetic (popPK) analysis was performed with MonolixSuite® 2024R1 (Lixoft, France). Model‐based simulations were used to predict trough concentration ( C _min ) and the area under the concentration–time curve over 24 h (AUC ₂₄ ) for the recommended dosage regimens, as a function of covariates. An exploratory pharmacokinetic/pharmacodynamic analysis was conducted in the overall cohort. Ruxolitinib PK was characterized by a marked between‐subject variability in clearance (45%). Strong cytochrome (CYP) 3A4 or dual CYP2C9/CYP3A4 inhibitors reduced clearance by 39%. At 10 mg twice daily, model‐based simulations showed CYP inhibitors increased median C _min and AUC ₂₄ by 2.9‐ and 1.7‐fold, respectively. Still, no significant exposure–efficacy relationship was identified. However, higher ruxolitinib exposure tended to be associated with increased toxicity in the overall population ( C _min and AUC ₂₄ , P ≈0.02–0.03). In clinical practice, ruxolitinib exposure shows substantial variability and is strongly affected by strong CYP inhibitors that are frequently co‐administered. Whilst no clear exposure–efficacy relationship was observed, higher exposure was linked to increased toxicity risk, arguing for careful dose adjustment.

Macozinone (MCZ, PBTZ169) is a potent clinical stage benzothiazinone antitubercular agent that covalently inhibits the essential mycobacterial flavoenzyme DprE1. In some mammals, MCZ undergoes reductive dearomatization to H ₂ MCZ, a Hydride Meisenheimer Complex, identified as the major circulating metabolite in humans. We demonstrate for the first time that the NADPH-dependent human prostaglandin reductases PTGR1 and PTGR2 catalyze MCZ dearomatization into H ₂ MCZ, resulting in loss of antimycobacterial activity. This reaction represents a heretofore undescribed host-mediated metabolic inactivation pathway for a therapeutic agent. Although H ₂ MCZ may constitute a transient reactive intermediate, ex vivo and cellular data indicate that it does not contribute to DprE1 inhibition in vivo . Pharmacological inhibition of PTGR1 and PTGR2 using diclofenac, indomethacin, dicumarol, or the selective inhibitor PTGR2-IN-1 suppresses H ₂ MCZ formation and partially restores MCZ antimycobacterial activity in vitro . Together, our findings uncover a previously unrecognized noncanonical enzymatic mechanism of drug metabolism involving dearomatization in humans. Targeting prostaglandin reductases may represent a strategy to enhance benzothiazinone exposure and efficacy.

Background and Objective Levosimendan is an inotrope and vasodilator agent commonly used in critical care, particularly to facilitate weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO). However, critical illness and ECMO may affect levosimendan and its clinically relevant metabolites’ pharmacokinetics, potentially compromising circulating exposure and efficacy. There are limited data on levosimendan pharmacokinetics in critically ill patients, including those on VA-ECMO, thus emphasising the need for further research in this area. The aim of this study was to characterise the pharmacokinetic profile of levosimendan and its metabolites OR-1855 and OR-1896 in both critically ill adults and neonates/infants on VA-ECMO. Methods We conducted a bicentric, prospective, observational, pharmacokinetic study in critically ill adults and neonates/infants on VA-ECMO receiving levosimendan. Dosage history, sampling and clinical information were gathered. Samples were analysed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry using a validated highly sensitive method. A population pharmacokinetic model describing levosimendan and its metabolites OR-1855 (inactive) and OR-1896 (active, long-lasting) was developed using non-linear mixed-effects modelling (NONMEM). Model-based simulations were performed to compare exposures produced by various dosing scenarios. Results Twenty-one patients, 15 adults, three neonates and three infants, provided 155 blood samples. In adults, levosimendan was started at a rate of 0.05 µg/kg/min for 1–4 h, then increased to maintenance doses reaching 0.1 (n = 9), 0.15 (n = 3) or 0.2 (n = 3) µg/kg/min for a total infusion time of approximately 24 h. The neonates/infants received a continuous infusion of 0.1 µg/kg/min for 48 h. A two-compartment model best characterised levosimendan pharmacokinetics, with a transit compartment adequately describing the metabolites’ delayed synthesis. The transformation of OR-1855 into OR-1896 was 3.7-fold slower in neonates/infants than in adults. Model-based simulations using a standard 0.1-µg/kg/min regimen for 24 and 48 h in adults and neonates/infants, respectively, achieved lower levosimendan and metabolite concentrations in neonates/infants. Simulations using a 48-h infusion of 0.2 µg/kg/min in neonates/infants predict levosimendan concentrations comparable to those in adults receiving a 0.1-µg/kg/min maintenance dose. However, in this scenario, OR-1896 concentrations would remain considerably lower than in adults. Conclusions Our data indicate that levosimendan and its metabolites exhibit altered the pharmacokinetics in neonates/infants on VA-ECMO. Although some of these changes may be associated with ECMO, definitive conclusions on causality cannot be drawn, as age-dependent specific physiology and critically ill conditions may also contribute. These findings support the consideration of dose optimisation in this population. In adults, levosimendan pharmacokinetics seem unaffected, although metabolite concentrations appear slightly reduced compared with non-critically ill patients with heart failure. Graphical Abstract

Background: This review re-evaluates therapeutic drug monitoring (TDM) by comparing the current analytical and subsequent clinical interpretation capabilities of hospital or community medical laboratories with the emerging potential of point-of-care (POC) devices, which could become increasingly utilized in hospital wards, day-hospital units, and outpatient clinic settings. Methods: A narrative review was conducted to identify publications that best illustrate the current trends in the development of POC TDM. Results: The latest scientific and technical literature indicates that POC devices for determining drug concentrations in clinical samples are approaching the market. Several technologies are now available to develop portable sensors capable of rapidly returning concentration measurements. Interfacing these methods with artificial intelligence-based pattern recognition may enhance the identification and quantification of drugs. However, once the drug concentration is accurately measured using a portable device, dosage adjustments require consideration of the drug's pharmacokinetics and the patient's characteristics. This is accounted for in the mathematical approaches underlying model-informed precision dosing, which consider inter- and intra-individual variability and provide recommendations for treatment adjustments. These complexities necessitate the use of digital technologies, including graphical interfaces, machine learning approaches, and secure connectivity, to enhance the application of TDM in clinical practice. Conclusions: Promising emerging technologies have considerable potential to expand TDM to cover a wide range of drugs, making precision medicine accessible to many patients.

Janus kinase inhibitors (JAKIs) emerged as novel therapies for a wide range of autoimmune and myeloproliferative neoplasms. JAKIs have remarkable clinical effectiveness, but emerging safety concerns have sparked interest in precision dosing approaches and the role of therapeutic drug monitoring (TDM) remains largely unexplored. This review summarizes the mechanisms of action, indications and adverse effects of approved JAKIs in Switzerland, namely, abrocitinib, baricitinib, momelotinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib. We discussed factors that impact the pharmacokinetics of JAKIs, as well as exposure - efficacy and toxicity relationships, to evaluate whether JAKIs are suitable candidates for TDM. Regulatory documents and a PubMed search using the terms 'drug monitoring,' 'pharmacokinetics,' and 'JAKIs (incl. abrocitinib, baricitinib, momelotinib, ritlecitinib, ruxolitinib, tofacitinib, and upadacitinib)' were used to compile data until March 2025. JAKIs meet the criteria for TDM as they have marked inter-individual pharmacokinetic variability, narrow therapeutic margins and exposure - response relationships. Implementing TDM in clinical practice requires to establish target concentration ranges associated with efficacy and toxicity, along with a better understanding of the pharmacokinetics of JAKIs in real-life settings.

Background: Janus kinase inhibitors (JAKIs) are small molecules used orally to treat inflammatory and hematological disorders. They have demonstrated impressive efficacy across multiple indications. However, concerns have emerged regarding their safety profile. Despite their growing clinical use, therapeutic drug monitoring is not yet established for JAKIs, but it could help address exposure-dependent efficacy and tolerability issues through individualized treatment approaches. Objective: This protocol aims to characterize the pharmacokinetics of the 6 most prescribed JAKIs in Switzerland (abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib) and identify factors influencing drug exposure. It seeks to explore exposure-response relationships to assess the impact of drug exposure markers on efficacy and safety. Ultimately, these findings will contribute to establishing therapeutic intervals. Methods: This prospective observational study, conducted throughout Switzerland, was approved by the Cantonal Ethics Committee in August 2023. Consenting adults (aged ≥18 years) who are capable of judgment and who are prescribed JAKIs are enrolled in the study, either for sparse sampling during routine medical visits to collect trough or random plasma concentrations or for a detailed pharmacokinetic substudy involving serial blood sampling over an 8-hour period. The characterization of JAKI pharmacokinetics, including associated variability and the effect of specific covariates, such as age, body weight, BMI, sex, disease type, drug-drug interactions, or concomitant pathophysiological conditions, will be performed using nonlinear mixed effect modeling techniques. Relationships between JAKI exposure and efficacy and safety will be assessed. Results: By August 2024, a total of 276 blood samples were collected from 107 patients, the majority being female individuals (n=62, 57.9%). The patients had a median age of 51 (range 17-87) years and a median body weight of 69 (range 39-132) kg. Most patients recruited were taking ruxolitinib (n=44, 41.1%), upadacitinib (n=39, 36.4%), or baricitinib (n=11, 10.3%). Conclusions: The framework of the study will allow the characterization of the pharmacokinetic profiles of JAKIs and their variability in real-world conditions. On the basis of novel therapeutic drug monitoring approaches, we expect to explore the relationship between drug exposure, treatment response, and tolerability, providing essential information for precise dose optimization. International Registered Report Identifier (IRRID): RR1-10.2196/70312

Cystic fibrosis (CF) is a life-threatening disorder caused by mutations in the CFTR gene, leading to defective chloride ion transport and thickened mucus in the respiratory and gastrointestinal systems. CFTR modulators, including ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have improved patient outcomes, but interindividual pharmacokinetic variability and potential drug–drug interactions require therapeutic drug monitoring (TDM) for optimal efficacy and safety. In this context, a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simultaneous quantification of CFTR modulators and their major active metabolites in human plasma to support pharmacokinetic studies and routine TDM. The multiplex LC-MS/MS assay was established using plasma protein precipitation, followed by chromatographic separation on an Xselect HSS T3 (Waters^®) column and positive electrospray ionization mode detection. The method was validated based on FDA and EMA guidelines for specificity, linearity, accuracy (89.8–107.8%), repeatability (1.1–8.1%), intermediate fidelity (1.3–10.9%), matrix effects, and stability, demonstrating a robust performance with excellent precision and accuracy. International interlaboratory comparisons confirmed the reliability of the assay. The developed method can be applied for the clinical monitoring of caftors’ plasma concentrations and preliminary data suggest that it can also be applied to alternative matrices, such as breast milk. This method will serve to characterize caftors’ pharmacokinetic variability and monitor drug–drug interactions to further refine personalized dosing strategies and enhance precision medicine treatments for patients with CF.

Cystic fibrosis (CF) is a life-threatening disorder caused by mutations in the CFTR gene, leading to defective chloride ion transport and thickened mucus in the respiratory and gastrointestinal systems. CFTR modulators, including ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have improved patient outcomes, but interindividual pharmacokinetic variability and potential drug-drug interactions require therapeutic drug monitoring (TDM) for optimal efficacy and safety. In this context, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the simul-taneous quantification of CFTR modulators and their major active metabolites in human plasma to support pharmacokinetic studies and routine TDM. The multiplex LC-MS/MS assay was established using plasma protein precipitation, followed by chromatographic separation on an Xselect HSS T3 column and positive electrospray ionization mode detec-tion. The method was validated based on FDA and EMA guidelines for specificity, linear-ity, accuracy, precision, matrix effects, and stability, demonstrating robust performance with excellent precision and accuracy. International interlaboratory comparisons con-firmed the reliability of the assay. The developed method has been applied for monitoring caftors plasma levels for patient TDM and also to research studies in alternative matrices such as breast milk. Future studies will help at characterizing caftors pharmacokinetic variability in patients and drug-drug interactions to further refine personalized dosing strategies.