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This document discusses the use of the lipemia index (L-index) as a potential tool for identifying patients with monoclonal gammopathy. The study found that the L-index had good specificity but low sensitivity for detecting M-proteins in serum and plasma samples. The accuracy of the L-index varied depending on the type of M-protein, and there was a low concordance between plasma and serum L-index values. The article suggests that the L-index test could be useful for identifying IgM plasma cell disorders, but further research is needed to improve its diagnostic performance. [Extracted from the article]

Apixaban and rivaroxaban have first-line use for many patients needing anticoagulation for venous thromboembolism (VTE). The pharmacokinetics of these drugs in non-obese subjects have been extensively studied, and, while changes in pharmacokinetics have been documented in obese patients, data remain scarce for these anticoagulants. The aim of this study was to perform an external validation of published population pharmacokinetic (PPK) models of apixaban and rivaroxaban in a cohort of obese patients with VTE. A literature search was conducted in the PubMed/MEDLINE, Scopus, and Embase databases following the PRISMA statement. External validation was performed using MonolixSuite software, using prediction-based and simulation-based diagnostics. An external validation dataset from the university hospitals of Brest and Rennes, France, included 116 apixaban pharmacokinetic samples from 69 patients and 121 rivaroxaban samples from 81 patients. Five PPK models of apixaban and 16 models of rivaroxaban were included, according to the inclusion criteria of the study. Two of the apixaban PPK models presented acceptable performances, whereas no rivaroxaban PPK model did. This study identified two published models of apixaban applicable to apixaban in obese patients with VTE. However, none of the rivaroxaban models evaluated were applicable. Dedicated studies appear necessary to elucidate rivaroxaban pharmacokinetics in this population. [ABSTRACT FROM AUTHOR]

Until recently, itch pathophysiology was poorly understood and treatments were poorly effective in relieving itch. Current progress in our knowledge of the itch processing, the numerous mediators and receptors involved has led to a large variety of possible therapeutic pathways. Currently, inhibitors of IL‐31, IL‐4/13, NK1 receptors, opioids and cannabinoids, JAK, PDE4 or TRP are the main compounds involved in clinical trials. However, many new targets, such as Mas‐related GPCRs and unexpected new pathways need to be also explored. [ABSTRACT FROM AUTHOR]

Background: The detection of monoclonal immunoglobulins (MIg) is a key element in the diagnosis of monoclonal gammopathies. Methods: Here we report two cases of high concentration serum IgM-kappa MIgs (6.4 g/L and 6.8 g/L) not detected with capillary electrophoresis (CE). A systematic literature search was conducted to assess the sensitivity of CE to detect MIgs. Results: The CE sensitivity to detect MIgs did not exceed 0.9 to 0.95 compared to immunofixation as standard. On the one hand, MIgs with blood concentrations below 1 g/L may be hidden by other serum proteins. On the other hand, some MIgs of high concentrations are not detected due to their insolubility in the electrophoresis buffer. Conclusions: Performing a second SPE with agarose gel electrophoresis method or modifying buffer properties may reveal some MIgs not detected by a first SPE alone. [ABSTRACT FROM AUTHOR]

The prevalence of obesity has been steadily increasing in recent years worldwide. At the same time bariatric surgery, the best therapeutic strategy to date in terms of sustainable weight loss and improvement of associated comorbidities has been also increasing. However, these surgeries, whether primarily restrictive or malabsorptive, raise questions about the pharmacology of oral drugs. Among widely used drugs, anticoagulants are the referent therapy to treat some cardiovascular diseases such as atrial fibrillation and venous thromboembolism. How bariatric surgery may impact pharmacological properties of oral anticoagulants, and more specifically, direct oral anticoagulants (DOACs) are difficult to anticipate. In this review, we describe available data concerning the potential impact of bariatric surgery on the pharmacology of oral anticoagulants. The vitamin K antagonists (VKAs) requirements for the same international normalized ratio target are reduced after bariatric surgery. Limited data available for dabigatran 150 mg twice daily indicate a risk of insufficient efficacy in atrial fibrillation after gastric bypass due to probable impaired absorption. Data for rivaroxaban at the prophylactic dose of 10 mg per day suggest no impact of bariatric surgery from 3 days to 8 months post‐surgery. However, no conclusive data are available for other anticoagulants or the use of DOACs at therapeutic doses. To date, DOACs are not recommended in patients who have undergone bariatric surgery, because of limited available data. Pending new studies to confirm the predictable pharmacokinetics and safety of DOACs in this population, especially at therapeutic doses, VKAs remain the first option for chronic anticoagulation. [ABSTRACT FROM AUTHOR]

Background: Radioimmunoassays, which are often not automated and time-consuming, are gradually being replaced in medical laboratories by non-radioactive methods that need to be evaluated. The purpose was to compare the measurement of thyroid-stimulating hormone receptor antibodies (TRAb) by the new Brahms' kit using Kryptor TRACE technology and the Brahms' radioimmunoassay. Methods: We prospectively collected all samples from patients who received thyroid-stimulating hormone receptor antibodies testing in July 2018 at the University Hospital of Brest. The radioimmunoassay used was the Dynotest TRAK human by BRAHMS Diagnostica (Berlin, Germany). The Kryptor method used the BRAHMS TRAK human Kryptor kit performed with the Kryptor Compact Plus system. Results: The inter-assay coefficient variations for the radioimmunological and Kryptor methods were 11.07% and 8.36%, respectively, with the low level quality control and 8.36% and 4.38%, respectively, with the high level quality control. Forty-four patients were included in the study including thirty-two Graves' disease patients in follow-up. The sensitivity of the radioimmunological method for the detection of Graves' disease was 0.94 and the specificity was 0.73. The sensitivity of the Kryptor method was 0.91 and the specificity was 0.91. A non-proportional systematic bias in favor of higher values of TRAb concentrations with the radioimmunological method was observed: slope of 0.93 (0.74 - 1.07, 95% confidence interval) and an intercept of -0.69 IU/L (-1.58 to -0.30, 95% confidence interval). Compared to the Kryptor method, the radioimmunological method tends to overestimate TRAb concentrations by up to 120%. Conclusions: The fully automated Brahms Kryptor kit using TRACE technology to measure TRAb reduces sampling time and intra- as well as inter-assay variations. The Kryptor kit underestimates the results of TRAb leading to a lower sensitivity and higher specificity compared to the radioimmunoassay. Thus, the new Brahms Kryptor kit has good laboratory performances but the interpretation of the results must still be performed with caution. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are a new class of monoclonal antibodies that amplify T-cell-mediated immune responses against cancer cells. The introduction of these new drugs, first anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and then anti-programmed death-1 (anti-PD1), was a major improvement in the treatment of advanced or metastatic melanoma, a highly immunogenic tumour. The development strategy for immune checkpoint immunotherapies differed from that traditionally used for cytotoxic therapies in oncology. The choices of doses at which to conduct clinical trials, and subsequently the choice of doses at which to use these new therapies, were not based on the identification of a maximum tolerated dose from dose-escalation studies; thus, pharmacokinetic and pharmacokinetic-pharmacodynamic modelling was essential. The studies conducted have shown that the pharmacokinetics of ipilimumab were linear and not time-dependent. In addition, there was a correlation between the trough concentrations of ipilimumab and its therapeutic efficacy. On the contrary, the anti-PD1 immunotherapies nivolumab and pembrolizumab had time-dependent pharmacokinetics. Their therapeutic efficacy was not related to their trough concentration, but there was a correlation between the clearance of anti-PD1 and the survival of melanoma patients. This review highlights the complexity of interpreting the exposure-response relationships of these agents. Further studies are needed to assess the value of therapeutic drug monitoring of immune checkpoint inhibitors in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

The article offers information on the Vancomycin, a bactericidal glycopeptide antibiotic used to treat systemic infections caused by methicillin-resistant Staphylococcus aureus (MRSA), penicillin resistant streptococci or enterococci; and mentions that Vancomycin in the sample competes with acridinium ester-labelled vancomycin for a limited amount of anti-vancomycin monoclonal mouse antibody covalently bound to paramagnetic particles.

Model-informed precision dosing is being increasingly used to improve therapeutic drug monitoring. To meet this need, several tools have been developed, but open-source software remains uncommon. Posologyr is a free and open-source R package developed to enable Bayesian individual parameter estimation and dose individualization. Before using it for clinical practice, performance validation is mandatory. The estimation functions implemented in posologyr were benchmarked against reference software products on a wide variety of models and pharmacokinetic profiles: 35 population pharmacokinetic models, with 4.000 simulated subjects by model. Maximum A Posteriori (MAP) estimates were compared to NONMEM post hoc estimates, and full posterior distributions were compared to Monolix conditional distribution estimates. The performance of MAP estimation was excellent in 98.7% of the cases. Considering the full posterior distributions of individual parameters, the bias on dosage adjustment proposals was acceptable in 97% of cases with a median bias of 0.65%. These results confirmed the ability of posologyr to serve as a basis for the development of future Bayesian dose individualization tools. [ABSTRACT FROM AUTHOR]

The article discusses the application of extracorporeal membrane oxygenation (ECMO) in cardiopulmonary disease. Topics discussed include alteration of drug's pharmacokinetics (PK) due to ECMO increasing risk of toxicity, maintaining the concentration of antibacterial drug above the minimum inhibitory concentration to ensure success of treatment, adsorption of drug being dependent on duration of use, and drugs used by ECMO patients such as cephalosporins and carbapenems having no effect on PK.

Roscovitine (Seliciclib), a new protein kinase inhibitor, was administered orally to adult patients with cystic fibrosis for the first time in the ROSCO-CF trial, a dose-escalation, phase IIa, randomized, controlled trial. Extensive pharmacokinetic sampling was performed up to 12 h after the first oral dose. Roscovitine and its main metabolite M3 were quantified by liquid chromatography coupled with tandem mass spectrometry. The pharmacokinetics analyses were performed by non-linear mixed effects modelling. Monte Carlo simulations were performed to assess the impact of dose on the pharmacokinetics of oral roscovitine. Twenty-three patients received oral doses ranging from 200 to 800 mg of roscovitine and 138 data points were available for both roscovitine and M3 concentrations. The pharmacokinetics was best described by a two-compartment parent-metabolite model, with a complex saturable absorption process modelled as the sum of Gaussian inverse density functions. The Monte Carlo simulations showed a dose-dependent and saturable first-pass effect leading to pre-systemic formation of M3. The treatment with proton-pump inhibitors reduced the rate of absorption of oral roscovitine. The pharmacokinetics of oral roscovitine in adult patients with cystic fibrosis was non-linear and showed significant inter-individual variability. A repeat-dose study will be required to assess the inter-occasional variability of its pharmacokinetics. [ABSTRACT FROM AUTHOR]