Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C <sub>max</sub> ) and trough concentration (C <sub>trough</sub> ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Pathogenesis and treatment of chronic pulmonary disease

Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients

Abstract The pathobiology of respiratory failure in COVID-19 consists of a complex interplay between viral cytopathic effects and a dysregulated host immune response. In critically ill patients, imatinib treatment demonstrated potential for reducing invasive ventilation duration and mortality. Here, we perform longitudinal profiling of 6385 plasma proteins in 318 hospitalised patients to investigate the biological processes involved in critical COVID-19, and assess the effects of imatinib treatment. Nine proteins measured at hospital admission accurately predict critical illness development. Next to dysregulation of inflammation, critical illness is characterised by pathways involving cellular adhesion, extracellular matrix turnover and tissue remodelling. Imatinib treatment attenuates protein perturbations associated with inflammation and extracellular matrix turnover. These proteomic alterations are contextualised using external pulmonary RNA-sequencing data of deceased COVID-19 patients and imatinib-treated Syrian hamsters. Together, we show that alveolar capillary barrier disruption in critical COVID-19 is reflected in the plasma proteome, and is attenuated with imatinib treatment. This study comprises a secondary analysis of both clinical data and plasma samples derived from a clinical trial that was registered with the EU Clinical Trials Register (EudraCT 2020–001236–10, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001236-10/NL ) and Netherlands Trial Register (NL8491, https://www.trialregister.nl/trial/8491 )

Voorspellende waarde VMS-thema 'Kwetsbare ouderen': delirium, valincidenten en overlijden bij oudere ziekenhuispatiënten

OBJECTIVE: To determine the predictive value of safety management system (VMS) screening questions for falling, delirium, and mortality, as punt down in the VMS theme 'Frail elderly'. DESIGN: Retrospective observational study. METHOD: We selected all patients ≥ 70 years who were admitted to non-ICU wards at the Deventer Hospital, the Netherlands, for at least 24 hours between 28 March 2011 and 10 June 2011. On admission, patients were screened with the VMS instrument by a researcher. Delirium and falls were recorded during hospitalisation. Six months after hospitalisation, data on mortality were collected. RESULTS: We included 688 patients with a median age of 78.7 (range: 70.0-97.1); 50.7% was male. The sensitivity of the screening for delirium risk was 82%, the specificity 62%. The sensitivity of the screening for risk of falling was 63%, the specificity 65%. Independent predictors for mortality within 6 months were delirium risk (odds ratio (OR): 2.3; 95% CI 1.1-3.2), malnutrition (OR: 2.1; 95% CI 1.3-3.5), admission to a non-surgical ward (OR: 3.0; 95% CI 1.8-5.1), and older age (OR: 1.1; 95%CI 1.0-1.1). Patients classified by the VMS theme 'Frail elderly' as having more risk factors had a higher risk of dying (p < 0.001). CONCLUSIONS: The VMS screening for delirium is a reasonably reliable instrument for identifying those elderly people with a high risk of developing this condition; the VMS sensitivity for fall risk is moderate. The number of positive VMS risk factors correlates with mortality and may therefore be regarded as a measure of frailty

Voorspellende waarde VMS-thema 'Kwetsbare ouderen'

To determine the predictive value of safety management system (VMS) screening questions for falling, delirium, and mortality, as punt down in the VMS theme 'Frail elderly'. Retrospective observational study. We selected all patients ≥ 70 years who were admitted to non-ICU wards at the Deventer Hospital, the Netherlands, for at least 24 hours between 28 March 2011 and 10 June 2011. On admission, patients were screened with the VMS instrument by a researcher. Delirium and falls were recorded during hospitalisation. Six months after hospitalisation, data on mortality were collected. We included 688 patients with a median age of 78.7 (range: 70.0-97.1); 50.7% was male. The sensitivity of the screening for delirium risk was 82%, the specificity 62%. The sensitivity of the screening for risk of falling was 63%, the specificity 65%. Independent predictors for mortality within 6 months were delirium risk (odds ratio (OR): 2.3; 95% CI 1.1-3.2), malnutrition (OR: 2.1; 95% CI 1.3-3.5), admission to a non-surgical ward (OR: 3.0; 95% CI 1.8-5.1), and older age (OR: 1.1; 95%CI 1.0-1.1). Patients classified by the VMS theme 'Frail elderly' as having more risk factors had a higher risk of dying (p < 0.001). The VMS screening for delirium is a reasonably reliable instrument for identifying those elderly people with a high risk of developing this condition; the VMS sensitivity for fall risk is moderate. The number of positive VMS risk factors correlates with mortality and may therefore be regarded as a measure of frailt