15 results on '"Caryn M Upton"'
Search Results
2. Reproducibility in pharmacometrics applied in a phase III trial of BCG-vaccination for COVID-19
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Rob C. van Wijk, Laurynas Mockeliunas, Gerben van den Hoogen, Caryn M. Upton, Andreas H. Diacon, and Ulrika S. H. Simonsson
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Medicine ,Science - Abstract
Abstract Large clinical trials often generate complex and large datasets which need to be presented frequently throughout the trial for interim analysis or to inform a data safety monitory board (DSMB). In addition, reliable and traceability are required to ensure reproducibility in pharmacometric data analysis. A reproducible pharmacometric analysis workflow was developed during a large clinical trial involving 1000 participants over one year testing Bacillus Calmette-Guérin (BCG) (re)vaccination in coronavirus disease 2019 (COVID-19) morbidity and mortality in frontline health care workers. The workflow was designed to review data iteratively during the trial, compile frequent reports to the DSMB, and prepare for rapid pharmacometric analysis. Clinical trial datasets (n = 41) were transferred iteratively throughout the trial for review. An RMarkdown based pharmacometric processing script was written to automatically generate reports for evaluation by the DSMB. Reports were compiled, reviewed, and sent to the DSMB on average three days after the data cut-off, reflecting the trial progress in real-time. The script was also utilized to prepare for the trial pharmacometric analyses. The same source data was used to create analysis datasets in NONMEM format and to support model script development. The primary endpoint analysis was completed three days after data lock and unblinding, and the secondary endpoint analyses two weeks later. The constructive collaboration between clinical, data management, and pharmacometric teams enabled this efficient, timely, and reproducible pharmacometrics workflow.
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- 2023
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3. Seasonal influence on respiratory tract infection severity including COVID‐19 quantified through Markov Chain modeling
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Rob C. vanWijk, Laurynas Mockeliunas, Caryn M. Upton, Jonathan Peter, Andreas H. Diacon, and Ulrika S. H. Simonsson
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Respiratory tract infections (RTIs) are a burden to global health, but their characterization is complicated by the influence of seasonality on incidence and severity. The Re‐BCG‐CoV‐19 trial (NCT04379336) assessed BCG (re)vaccination for protection from coronavirus disease 2019 (COVID‐19) and recorded 958 RTIs in 574 individuals followed over 1 year. We characterized the probability of RTI occurrence and severity using a Markov model with health scores (HSs) for four states of symptom severity. Covariate analysis on the transition probability between HSs explored the influence of demographics, medical history, severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), or influenza vaccinations, which became available during the trial, SARS‐CoV‐2 serology, and epidemiology‐informed seasonal influence of infection pressure represented as regional COVID‐19 pandemic waves, as well as BCG (re)vaccination. The infection pressure reflecting the pandemic waves increased the risk of RTI symptom development, whereas the presence of SARS‐CoV‐2 antibodies protected against RTI symptom development and increased the probability of symptom relief. Higher probability of symptom relief was also found in participants with African ethnicity and with male biological gender. SARS‐CoV‐2 or influenza vaccination reduced the probability of transitioning from mild to healthy symptoms. Model diagnostics over calendar‐time indicated that COVID‐19 cases were under‐reported during the first wave by an estimated 2.76‐fold. This trial was performed during the initial phase of the COVID‐19 pandemic in South Africa and the results reflect that situation. Using this unique clinical dataset of prospectively studied RTIs over the course of 1 year, our Markov Chain model was able to capture risk factors for RTI development and severity, including epidemiology‐informed infection pressure.
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- 2023
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4. Transrenal Mycobacterium tuberculosis DNA in pulmonary tuberculosis patients during the first 14 days of treatment
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Irina Kontsevaya, Jan Heyckendorf, Frauke Koops, Doris Hillemann, Torsten Goldmann, Caryn M. Upton, Veronique De Jager, Andreas Diacon, and Christoph Lange
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Mycobacterium tuberculosis ,early bactericidal activity ,anti-tuberculous treatment ,Microbiology ,QR1-502 - Abstract
ABSTRACT We assessed the performance of a novel real-time PCR-based transrenal DNA (trDNA) assay for the specific detection of Mycobacterium tuberculosis as a candidate marker of the early anti-tuberculosis therapy response. The study was performed on 288 urine samples from 72 tuberculosis patients collected at baseline and days 3, 7, and 14 of treatment with amoxicillin-clavulanic acid alone or in combination with meropenem, ertapenem, optimized-dose rifampicin, or standard treatment control in South Africa. trDNA was detected in one-third of the samples. The highest proportion of positive PCR results (cycle threshold < 36) was observed on days 3 and 7, reflecting the point in time when maximum bacterial killing and disintegration are expected. When analyzed by study arms, the trend was observed in groups treated with active antibiotics affecting cell wall integrity (meropenem, control) but not in inactive drugs (ertapenem, amoxicillin/clavulanic acid alone) or active drugs not affecting the cell wall (rifampicin). Overall, however, the trDNA assay did not correlate well with sputum culture-based decline of viable bacteria. This is possibly due to trDNA reflecting the killing of both culturable and non-culturable bacteria and should be explored further. IMPORTANCE This study presents the results of the evaluation of a novel method for the detection of Mycobacterium tuberculosis, the causative agent of tuberculosis, in urine. Detecting parts of the mycobacteria in urine is of particular interest as it allows us to use a sample that is easy to obtain and that does not require uncomfortable procedures or safety precautions like obtaining sputum for culture, which is the most commonly used sample in the diagnosis of tuberculosis. In certain groups of individuals who cannot produce sputum, for example, children, non-sputum-based methods have particular importance. We found that the method tested was able to detect bacterial killing by active antibiotics that disrupt the cell wall and lead to fragmentation of bacteria. However, the assay can't detect inactive bacteria or bacteria that are active with an intact cell wall.
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- 2023
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5. Risk Factors for COVID-19 and Respiratory Tract Infections during the Coronavirus Pandemic
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Laurynas Mockeliunas, Rob C. van Wijk, Caryn M. Upton, Jonathan Peter, Andreas H. Diacon, and Ulrika S. H. Simonsson
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risk factors ,respiratory tract infections ,COVID-19 ,time-to-event analysis ,pharmacometrics ,Medicine - Abstract
(1) Background: Some individuals are more susceptible to developing respiratory tract infections (RTIs) or coronavirus disease (COVID-19) than others. The aim of this work was to identify risk factors for symptomatic RTIs including COVID-19 and symptomatic COVID-19 during the coronavirus pandemic by using infection incidence, participant baseline, and regional COVID-19 burden data. (2) Methods: Data from a prospective study of 1000 frontline healthcare workers randomized to Bacillus Calmette–Guérin vaccination or placebo, and followed for one year, was analyzed. Parametric time-to-event analysis was performed to identify the risk factors associated with (a) non-specific symptomatic respiratory tract infections including COVID-19 (RTIs+COVID-19) and (b) symptomatic RTIs confirmed as COVID-19 using a polymerase chain reaction or antigen test (COVID-19). (3) Results: Job description of doctor or nurse (median hazard ratio [HR] 1.541 and 95% confidence interval [CI] 1.299–1.822), the reported COVID-19 burden (median HR 1.361 and 95% CI 1.260–1.469 for 1.4 COVID-19 cases per 10,000 capita), or a BMI > 30 kg/m2 (median HR 1.238 and 95% CI 1.132–1.336 for BMI of 35.4 kg/m2) increased the probability of RTIs+COVID-19, while positive SARS-CoV-2 serology at enrollment (median HR 0.583 and 95% CI 0.449–0.764) had the opposite effect. The reported COVID-19 burden (median HR 2.372 and 95% CI 2.116–2.662 for 1.4 COVID-19 cases per 10,000 capita) and a job description of doctor or nurse (median HR 1.679 and 95% CI 1.253–2.256) increased the probability of developing COVID-19, while smoking (median HR 0.428 and 95% CI 0.284–0.648) and positive SARS-CoV-2 serology at enrollment (median HR 0.076 and 95% CI 0.026–0.212) decreased it. (4) Conclusions: Nurses and doctors with obesity had the highest probability of developing RTIs including COVID-19. Non-smoking nurses and doctors had the highest probability of developing COVID-19 specifically. The reported COVID-19 burden increased the event probability, while positive SARS-CoV-2 IgG serology at enrollment decreased the probability of RTIs including COVID-19, and COVID-19 specifically.
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- 2024
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6. Standards for model-based early bactericidal activity analysis and sample size determination in tuberculosis drug development
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Laurynas Mockeliunas, Alan Faraj, Rob C. van Wijk, Caryn M. Upton, Gerben van den Hoogen, Andreas H. Diacon, and Ulrika S. H. Simonsson
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tuberculosis ,early bactericidal activity ,sample size ,pharmacometrics ,model-based analysis ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Background: A critical step in tuberculosis (TB) drug development is the Phase 2a early bactericidal activity (EBA) study which informs if a new drug or treatment has short-term activity in humans. The aim of this work was to present a standardized pharmacometric model-based early bactericidal activity analysis workflow and determine sample sizes needed to detect early bactericidal activity or a difference between treatment arms.Methods: Seven different steps were identified and developed for a standardized pharmacometric model-based early bactericidal activity analysis approach. Non-linear mixed effects modeling was applied and different scenarios were explored for the sample size calculations. The sample sizes needed to detect early bactericidal activity given different TTP slopes and associated variability was assessed. In addition, the sample sizes needed to detect effect differences between two treatments given the impact of different TTP slopes, variability in TTP slope and effect differences were evaluated.Results: The presented early bactericidal activity analysis approach incorporates estimate of early bactericidal activity with uncertainty through the model-based estimate of TTP slope, variability in TTP slope, impact of covariates and pharmacokinetics on drug efficacy. Further it allows for treatment comparison or dose optimization in Phase 2a. To detect early bactericidal activity with 80% power and at a 5% significance level, 13 and 8 participants/arm were required for a treatment with a TTP-EBA0-14 as low as 11 h when accounting for variability in pharmacokinetics and when variability in TTP slope was 104% [coefficient of variation (CV)] and 22%, respectively. Higher sample sizes are required for smaller early bactericidal activity and when pharmacokinetics is not accounted for. Based on sample size determinations to detect a difference between two groups, TTP slope, variability in TTP slope and effect difference between two treatment arms needs to be considered.Conclusion: In conclusion, a robust standardized pharmacometric model-based EBA analysis approach was established in close collaboration between microbiologists, clinicians and pharmacometricians. The work illustrates the importance of accounting for covariates and drug exposure in EBA analysis in order to increase the power of detecting early bactericidal activity for a single treatment arm as well as differences in EBA between treatments arms in Phase 2a trials of TB drug development.
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- 2023
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7. Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers: A double-blind, randomised, controlled, phase 3 trial
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Caryn M. Upton, Rob C. van Wijk, Laurynas Mockeliunas, Ulrika S.H. Simonsson, Kirsten McHarry, Gerben van den Hoogen, Chantal Muller, Arne von Delft, Helene-Mari van der Westhuizen, Reinout van Crevel, Gerhard Walzl, Pedro M. Baptista, Jonathan Peter, and Andreas H. Diacon
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COVID-19 ,BCG ,Respiratory tract infection ,Vaccine ,Tuberculosis ,Trained immunity ,Medicine (General) ,R5-920 - Abstract
Summary: Background: BCG vaccination prevents severe childhood tuberculosis (TB) and was introduced in South Africa in the 1950s. It is hypothesised that BCG trains the innate immune system by inducing epigenetic and functional reprogramming, thus providing non-specific protection from respiratory tract infections. We evaluated BCG for reduction of morbidity and mortality due to COVID-19 in healthcare workers in South Africa. Methods: This randomised, double-blind, placebo-controlled trial recruited healthcare workers at three facilities in the Western Cape, South Africa, unless unwell, pregnant, breastfeeding, immunocompromised, hypersensitivity to BCG, or undergoing experimental COVID-19 treatment. Participants received BCG or saline intradermally (1:1) and were contacted once every 4 weeks for 1 year. COVID-19 testing was guided by symptoms. Hospitalisation, COVID-19, and respiratory tract infections were assessed with Cox proportional hazard modelling and time-to-event analyses, and event severity with post hoc Markovian analysis. This study is registered with ClinicalTrials.gov, NCT04379336. Findings: Between May 4 and Oct 23, 2020, we enrolled 1000 healthcare workers with a median age of 39 years (IQR 30–49), 70·4% were female, 16·5% nurses, 14·4% medical doctors, 48·5% had latent TB, and 15·3% had evidence of prior SARS-CoV-2 exposure. Hospitalisation due to COVID-19 occurred in 15 participants (1·5%); ten (66·7%) in the BCG group and five (33·3%) in the placebo group, hazard ratio (HR) 2·0 (95% CI 0·69–5·9, p = 0·20), indicating no statistically significant protection. Similarly, BCG had no statistically significant effect on COVID-19 (p = 0·63, HR = 1·08, 95% CI 0·82–1·42). Two participants (0·2%) died from COVID-19 and two (0·2%) from other reasons, all in the placebo group. Interpretation: BCG did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalisation. Funding: Funding provided by EDCTP, grant number RIA2020EF-2968. Additional funding provided by private donors including: Mediclinic, Calavera Capital (Pty) Ltd, Thys Du Toit, Louis Stassen, The Ryan Foundation, and Dream World Investments 401 (Pty) Ltd. The computations were enabled by resources in project SNIC 2020–5–524 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement No. 2018–05,973.
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- 2022
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8. Cerebrospinal Fluid and Tuberculous Meningitis
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Caryn M Upton, Lubbe Wiesner, Kelly E Dooley, and Gary Maartens
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Microbiology (medical) ,Infectious Diseases - Published
- 2023
9. Pharmacokinetics of bedaquiline in cerebrospinal fluid (CSF) in patients with pulmonary tuberculosis (TB)
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Caryn M Upton, Chanel I Steele, Gary Maartens, Andreas H Diacon, Lubbe Wiesner, and Kelly E Dooley
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Male ,Pharmacology ,Microbiology (medical) ,Infectious Diseases ,Tuberculosis, Multidrug-Resistant ,Antitubercular Agents ,Humans ,Pharmacology (medical) ,Diarylquinolines ,Tuberculosis, Pulmonary ,Original Research - Abstract
Background With current treatment options most patients with CNS TB develop severe disability or die. Drug-resistant tuberculous meningitis is nearly uniformly fatal. Novel treatment strategies are needed. Bedaquiline, a potent anti-TB drug, has been reported to be absent from CSF in a single report. Objectives To explore the pharmacokinetics of bedaquiline and its M2 metabolite in the CSF of patients with pulmonary TB. Patients and methods Individuals with rifampicin-resistant pulmonary TB established on a 24 week course of treatment with bedaquiline underwent a lumbar puncture along with multiple blood sample collections over 24 h for CSF and plasma pharmacokinetic assessment, respectively. To capture the expected low bedaquiline and M2 concentrations (due to high protein binding in plasma) we optimized CSF collection and storage methods in vitro before concentrations were quantified via liquid chromatography with tandem MS. Results Seven male participants were enrolled, two with HIV coinfection. Using LoBind® tubes lined with a 5% BSA solution, bedaquiline and M2 could be accurately measured in CSF. Bedaquiline and M2 were present in all patients at all timepoints at concentrations similar to the estimated unbound fractions in plasma. Conclusions Bedaquiline and M2 penetrate freely into the CSF of pulmonary TB patients with a presumably intact blood–brain barrier. Clinical studies are urgently needed to determine whether bedaquiline can contribute meaningfully to the treatment of CNS TB.
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- 2022
10. Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis The COMRADE Randomized, Phase 2A Clinical Trial
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Veronique De Jager, Nikhil Gupte, Silvia Nunes, Grace L. Barnes, Rob Christiaan van Wijk, Joni Mostert, Susan E. Dorman, Ahmed A. Abulfathi, Caryn M. Upton, Alan Faraj, Eric L. Nuermberger, Gyanu Lamichhane, Elin M. Svensson, Ulrika S. H. Simonsson, Andreas H. Diacon, and Kelly E. Dooley
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Pulmonary and Respiratory Medicine ,Antitubercular Agents ,Amoxicillin ,Original Articles ,Meropenem ,Critical Care and Intensive Care Medicine ,All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Tuberculosis, Multidrug-Resistant ,Isoniazid ,Humans ,Drug Therapy, Combination ,Rifampin ,Tuberculosis, Pulmonary ,Clavulanic Acid - Abstract
RATIONALE: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. OBJECTIVES: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. METHODS: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0–14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. MEASUREMENTS AND MAIN RESULTS: Sixty participants enrolled. Median EBA(CFU0–14) counts (2.5th–97.5th percentiles) were 0.22 (0.12–0.33), 0.12 (0.057–0.21), 0.059 (0.033–0.097), and 0.053 (0.035–0.081); TTP increased by 0.34 (0.21–0.75), 0.11 (0.052–0.37), 0.094 (0.034–0.23), and 0.12 (0.04–0.41) (log(10) h), for arms C–F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. CONCLUSIONS: Bactericidal activity was greater with the World Health Organization–recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).
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- 2022
11. Early bactericidal activity studies for pulmonary tuberculosis: A systematic review of methodological aspects
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Simon E. Koele, Patrick P.J. Phillips, Caryn M. Upton, Jakko van Ingen, Ulrika S.H. Simonsson, Andreas H. Diacon, Rob E. Aarnoutse, and Elin M. Svensson
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Microbiology (medical) ,Infectious Medicine ,Infektionsmedicin ,General Medicine ,Early bactericidal activity ,Farmaceutiska vetenskaper ,Microbiology in the medical area ,Pharmaceutical Sciences ,Infectious Diseases ,All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Reporting ,Analysis methods ,Mikrobiologi inom det medicinska området ,Tuberculosis ,Pharmacology (medical) - Abstract
Contains fulltext : 292507.pdf (Publisher’s version ) (Open Access) A milestone in the development of novel antituberculosis drugs is the demonstration of early bactericidal activity (EBA) in a phase IIa clinical trial. The significant variability in measurements of bacterial load complicates data analysis in these trials. A systematic review and evaluation of methods for determination of EBA in pulmonary tuberculosis studies was undertaken. Bacterial load quantification biomarkers, reporting intervals, calculation methods, statistical testing, and handling of negative culture results were extracted. In total, 79 studies were identified in which EBA was determined. Colony-forming units on solid culture media and/or time-to-positivity in liquid media were the biomarkers used most often, reported in 72 (91%) and 34 (43%) studies, respectively. Twenty-two different reporting intervals were presented, and 12 different calculation methods for EBA were identified. Statistical testing for a significant EBA compared with no change was performed in 54 (68%) studies, and between-group testing was performed in 32 (41%) studies. Negative culture result handling was discussed in 34 (43%) studies. Notable variation was found in the analysis methods and reporting of EBA studies. A standardized and clearly reported analysis method, accounting for different levels of variability in the data, could aid the generalization of study results and facilitate comparison between drugs/regimens.
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- 2023
12. Liquid chromatography-tandem mass spectrometry analysis of delamanid and its metabolite in human cerebrospinal fluid using protein precipitation and on-line solid-phase extraction
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Marian T. Mazanhanga, Anton Joubert, Sandra A. Castel, Marthinus van der Merwe, Gary Maartens, Kelly E. Dooley, Caryn M. Upton, and Lubbe Wiesner
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Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Spectroscopy ,Analytical Chemistry - Published
- 2023
13. Bacillus Calmette-Guérin vaccine to reduce COVID-19 infections and hospitalisations in healthcare workers - a living systematic review and prospective ALL-IN meta-analysis of individual participant data from randomised controlled trials
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J.A. (Judith) ter Schure, Alexander Ly, Lisa Belin, Christine S. Benn, Marc J.M. Bonten, Jeffrey D. Cirillo, Johanna A.A. Damen, Inês Fronteira, Kelly D. Hendriks, Ana Paula Junqueira-Kipnis, André Kipnis, Odile Launay, Jose Euberto Mendez-Reyes, Judit Moldvay, Mihai G. Netea, Sebastian Nielsen, Caryn M. Upton, Gerben van den Hoogen, Jesper M. Weehuizen, Peter D. Grünwald, and C.H. (Henri) van Werkhoven
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infectious diseases - Abstract
BACKGROUNDThe objective is to determine the impact of the Bacillus Calmette-Guérin (BCG) vaccine compared to placebo or no vaccine on COVID-19 infections and hospitalisations in healthcare workers. We are using a living and prospective approach to Individual-Participant-Data (IPD) meta-analysis of ongoing studies based on the Anytime Live and Leading Interim (ALL-IN) meta-analysis statistical methodology.METHODSPlanned and ongoing randomised controlled trials were identified from trial registries and by snowballing (final elicitation: Oct 3 2022). The methodology was specified prospectively – with no trial results available – for trial inclusion as well as statistical analysis. Inclusion decisions were made collaboratively based on a risk-of-bias assessment by an external protocol review committee (Cochrane risk-of-bias tool adjusted for use on protocols), expected homogeneity in treatment effect, and agreement with the predetermined event definitions. The co-primary endpoints were incidence of COVID-19 infection and COVID-19-related hospital admission. Accumulating IPD from included trials was analysed sequentially using the exacte-value logrank test (at level α = 0.5% for infections and level α = 4.5% for hospitalisations) and anytime-valid 95%-confidence intervals (CIs) for the hazard ratio (HR) for a predetermined fixed-effects approach to meta-analysis (no measures of statistical heterogeneity). Infections were included if demonstrated by PCR tests, antigen tests or suggestive lung CTs. Participants were censored at date of first COVID-19-specific vaccination and two-stage analyses were performed in calendar time, with a stratification factor per trial.RESULTSSix trials were included in the primary analysis with 4 433 participants in total. Thee-values showed no evidence of a favourable effect of minimal clinically relevance (HR < 0.8) in comparison to the null (HR = 1) for COVID-19 infections, nor for COVID-19 hospitalisations (HR < 0.7 vs HR = 1). COVID-19 infection was observed in 251 participants receiving BCG and 244 participants not receiving BCG, HR 1.02 (anytime-valid 95%-CI 0.78-1.35). COVID-19 hospitalisations were observed in 13 participants receiving BCG and 7 not receiving BCG, resulting in an uninformative estimate (HR 1.88; anytime-valid 95%-CI 0.26-13.40).DISCUSSIONIt is highly unlikely that BCG has a clinically relevant effect on COVID-19 infections in healthcare workers. With only limited observations, no conclusion could be drawn for COVID-19 related hospitalisation. Due to the nature of ALL-IN meta-analysis, emerging data from new trials can be included without violating type-I error rates or interval coverage. We intend to keep this meta-analysis alive and up-to-date, as more trials report. For COVID-19 related hospitalisations, we do not expect enough future observations for a meaningful analysis. For BCG-mediated protection against COVID-19 infections, on the other hand, more observations could lead to a more precise estimate that concludes the meta-analysis for futility, meaning that the current interval excludes the HR of 0.8 predetermined as effect size of minimal clinical relevance.OTHERNo external funding. Preregistered at PROSPERO: CRD42021213069.
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- 2022
14. Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens
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Lénaïg Tanneau, Mats O. Karlsson, Susan L. Rosenkranz, Yoninah S. Cramer, Justin Shenje, Caryn M. Upton, Joel Morganroth, Andreas H. Diacon, Gary Maartens, Kelly E. Dooley, and Elin M. Svensson
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Pharmacology ,Electrocardiography ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,Heart Rate ,Nitroimidazoles ,Humans ,Pharmacology (medical) ,Pharmacology and Toxicology ,Diarylquinolines ,Farmakologi och toxikologi ,Oxazoles - Abstract
Contains fulltext : 283109.pdf (Publisher’s version ) (Open Access) Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens. Data were obtained from a trial where participants were randomized 1:1:1 to receive delamanid, bedaquiline, or delamanid + bedaquiline. The effect on QTcF of delamanid and/or its metabolite (DM-6705) and the pharmacodynamic interactions under coadministration were explored based on a published model between bedaquiline's metabolite (M2) and QTcF. The metabolites of each drug were found to be responsible for the drug-related QTcF prolongation. The final drug-effect model included a competitive interaction between M2 and DM-6705 acting on the same cardiac receptor and thereby reducing each other's apparent potency, by 28% (95% confidence interval (CI), 22-40%) for M2 and 33% (95% CI, 24-54%) for DM-6705. The generated combined effect was not greater but close to "additivity" in the analyzed concentration range. Predictions with the final model suggested a similar QT prolonging potential with simplified, once-daily dosing regimens compared with the approved regimens, with a maximum median change from baseline QTcF increase of 20 milliseconds in both regimens. The concentrations-QTcF relationship of the combination of bedaquiline and delamanid was best described by a competitive binding model involving the two main metabolites. Model predictions demonstrated that QTcF prolongation with simplified once daily regimens would be comparable to currently used dosing regimens.
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- 2022
15. Population Pharmacokinetics of Delamanid and its Main Metabolite DM-6705 in Drug-Resistant Tuberculosis Patients Receiving Delamanid Alone or Coadministered with Bedaquiline
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Lénaïg Tanneau, Mats O. Karlsson, Andreas H. Diacon, Justin Shenje, Jorge De Los Rios, Lubbe Wiesner, Caryn M. Upton, Kelly E. Dooley, Gary Maartens, and Elin M. Svensson
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Pharmacology ,Adult ,non-linear mixed effects model ,metabolite ,Antitubercular Agents ,HIV Infections ,delamanid ,Farmaceutiska vetenskaper ,Pharmaceutical Sciences ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,tuberculosis ,Nitroimidazoles ,Albumins ,Tuberculosis, Multidrug-Resistant ,Humans ,Pharmacology (medical) ,Diarylquinolines ,Oxazoles ,pharmacokinetics - Abstract
Contains fulltext : 283108.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVE: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered. METHODS: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling. RESULTS: Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV). CONCLUSIONS: This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.
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- 2022
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