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Frontiers in Pharmacology 2023Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a...
Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes. Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4. Viral levels showed a drop from 10 to 10 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration. To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.
PubMed: 37771727
DOI: 10.3389/fphar.2023.1211452 -
Pharmaceutics Nov 2023Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is...
Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC) (0.664 µg/mL) and >8 × PA-IC (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP.
PubMed: 38140050
DOI: 10.3390/pharmaceutics15122709 -
Kidney International Jun 2024Accurate assessment of the glomerular filtration rate (GFR) is crucial for researching kidney disease in rats. Although validation of methods that assess GFR is crucial,... (Comparative Study)
Comparative Study
Accurate assessment of the glomerular filtration rate (GFR) is crucial for researching kidney disease in rats. Although validation of methods that assess GFR is crucial, large-scale comparisons between different methods are lacking. Both transcutaneous GFR (tGFR) and a newly developed estimated GFR (eGFR) equation by our group provide a low-invasive approach enabling repeated measurements. The tGFR is a single bolus method using FITC-labeled sinistrin to measure GFR based on half-life of the transcutaneous signal, whilst the eGFR is based on urinary sinistrin clearance. Here, we retrospectively compared tGFR, using both 1- and 3- compartment models (tGFR_1c and tGFR_3c, respectively) to the eGFR in a historic cohort of 43 healthy male rats and 84 male rats with various models of chronic kidney disease. The eGFR was on average considerably lower than tGFR-1c and tGFR-3c (mean differences 855 and 216 μL/min, respectively) and only 20 and 47% of measurements were within 30% of each other, respectively. The relative difference between eGFR and tGFR was highest in rats with the lowest GFR. Possible explanations for the divergence are problems inherent to tGFR, such as technical issues with signal measurement, description of the signal kinetics, and translation of half-life to tGFR, which depends on distribution volume. The unknown impact of isoflurane anesthesia used in determining mGFR remains a limiting factor. Thus, our study shows that there is a severe disagreement between GFR measured by tGFR and eGFR, stressing the need for more rigorous validation of the tGFR and possible adjustments to the underlying technique.
Topics: Animals; Glomerular Filtration Rate; Male; Renal Insufficiency, Chronic; Disease Models, Animal; Rats; Kidney; Rats, Sprague-Dawley; Retrospective Studies; Fluorescein-5-isothiocyanate; Reproducibility of Results; Renal Elimination; Fluoresceins; Oligosaccharides
PubMed: 38514000
DOI: 10.1016/j.kint.2024.02.020 -
Journal of Affective Disorders Aug 2023The choice of antidepressants for initial pharmacological treatment of depression in older adults and associated patients' characteristics are understudied. We aimed to...
Do sociodemographic and clinical factors affect the selection of initial antidepressant treatment for depression in older adults? Results from a nationwide descriptive study in Denmark.
BACKGROUND
The choice of antidepressants for initial pharmacological treatment of depression in older adults and associated patients' characteristics are understudied. We aimed to describe the first selected antidepressant (first-choice) for depression in older adults (≥65 years) and whether patients' sociodemographic and clinical characteristics influence selecting an alternative first-choice (any other antidepressant than the nationally recommended first-choice sertraline) in Denmark.
METHODS
Register-based cross-sectional study including all older adults who redeemed their first antidepressant prescription for depression at community pharmacies in Denmark in 2015-2019. We analyzed the effect of patients' characteristics on the first-choice antidepressant selection using multinomial logistic regression.
RESULTS
Among 34,337 older adults with a first antidepressant-prescription, over two-thirds filled alternative first-choice antidepressants than sertraline (28.9 %): escitalopram or citalopram (30.3 %) or mirtazapine (34.4 %). Socially disadvantaged older adults (e.g., with short educational attainment, being single, or of non-western ethnicity) and clinically vulnerable older adults (e.g., having somatic diagnoses and hospital contacts) were more likely to use alternative first-choice antidepressants.
LIMITATIONS
Information on prescribers and in-hospital medications was not included in this study.
CONCLUSIONS
Further investigation of the first antidepressant selection and its impact on depression treatment outcomes in older adults is necessary. Moreover, for older patients, national guidelines on depression treatment should be more specific.
ARTICLE SUMMARY
Antidepressant selection for initial pharmacological treatment of depression in older adults can be difficult due to comorbidity, polypharmacy, and age-related changes in pharmacokinetics and pharmacodynamics. Real-world evidence/knowledge on first-choice antidepressant selection and associated user characteristics are rare. This Danish register-based cross-sectional study found over two-thirds of older adults filled alternative antidepressants (primarily escitalopram/citalopram or mirtazapine) than nationally recommended first-choice sertraline for depression treatment and identified wide-ranging sociodemographic and clinical factors influencing the first antidepressant selection.
Topics: Humans; Aged; Sertraline; Citalopram; Depression; Mirtazapine; Escitalopram; Cross-Sectional Studies; Antidepressive Agents; Denmark
PubMed: 37146907
DOI: 10.1016/j.jad.2023.04.110 -
PloS One 2024Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine... (Clinical Trial)
Clinical Trial
Mesalazine is a well-established treatment for ulcerative colitis by oral or topical administration. However, the pharmacokinetic (PK) and safety profiles of mesalazine administered by an enema has not been clarified in Chinese population. We conducted an open-label study to assess the PK and safety profiles of mesalazine in 11 healthy Chinese subjects after receiving mesalazine enema (1 g/100 mL) once daily for 7 consecutive days. Blood and urine samples were collected for assay of mesalazine and N-acetyl mesalazine by liquid chromatography-tandem mass spectrometry. The PK and safety data were summarized using descriptive statistics. The mean (standard deviation) maximum plasma concentration (Cmax), area under plasma drug concentration-time curve from time 0 to the last measurable plasma concentration time point (AUC0-t) and elimination half-life (t1/2) of mesalazine were 1007.64 (369.00) ng/mL, 9608.59 (3533.08) h·ng/mL and 3.33 (1.99) h, respectively after the first dose administration. In multiple-dose study, the estimated accumulation factor of mesalazine was 1.09. The cumulative urinary excretion rate of parent and major metabolite of mesalazine was 27.77%. After the last doe administration, 2.21% of the administered dose was excreted as mesalazine and 24.47% as N-acetyl mesalazine in urine within 24 h. Overall, 9 adverse events (AEs) were reported in 4 of the 11 subjects (36.4%), including oral ulcer, toothache, upper respiratory tract infection (1 each) and laboratory abnormalities (6 cases). All AEs were mild and recovered spontaneously without treatment, and were not considered as related to mesalazine. Mesalazine enema (1 g/100 mL) was safe and well tolerated in healthy Chinese subjects. These findings support further clinical trials in Chinese patients. Trial registration: This trial was registered to Chinese Clinical Trial Registry (ChiCTR) at https://www.chictr.org.cn (registration number: ChiCTR2300073148).
Topics: Humans; Administration, Oral; Area Under Curve; China; Chromatography, Liquid; Dose-Response Relationship, Drug; Healthy Volunteers; Mesalamine; Tandem Mass Spectrometry
PubMed: 38306390
DOI: 10.1371/journal.pone.0296940 -
Infection Dec 2023Posaconazole is an antifungal drug currently being used for prophylaxis and treatment of invasive fungal infections such as aspergillosis. To date, therapeutic drug...
PURPOSE
Posaconazole is an antifungal drug currently being used for prophylaxis and treatment of invasive fungal infections such as aspergillosis. To date, therapeutic drug monitoring (TDM) of posaconazole is recommended with the use of oral suspension, but the potential need of TDM with the use of IV formulations is rising. Therefore, we aimed to investigate the pharmacokinetics of IV posaconazole in critically ill patients.
METHODS
In a prospective study, we analysed 168 consecutivelly collected posaconazole levels from 10 critically ill patients drawn during a 7 day curse. Posaconazole concentrations were measured using a chromatographic method. Demographic and laboratory data were collected, and the data was analysed using descriptive statistics.
RESULTS
We included 168 posaconazole levels, resulting in a median trough of 0.62 [0.29-1.05] mg/L with 58% not reaching the suggested target of 0.5 mg/L for fungal prophylaxis. Moreover, 74% of the trough levels were under the target of 1 mg/L which is proposed for the treatment of aspergillosis.
CONCLUSION
Posaconazole exposure is highly variable in critically ill patients resulting in potentially insufficient drug concentrations in many cases. TDM is highly recommended to identify and avoid underexposure.
TRIAL REGISTRATION NUMBER
NCT05275179, March 11, 2022.
Topics: Humans; Prospective Studies; Critical Illness; Antifungal Agents; Aspergillosis; Intensive Care Units
PubMed: 37498488
DOI: 10.1007/s15010-023-02078-9 -
Therapeutic Drug Monitoring Dec 2023The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow...
BACKGROUND
The clinical outcomes of busulfan-based conditioning regimens for hematopoietic cell transplantation (HCT) have been improved by personalizing the doses to target narrow busulfan plasma exposure. An interlaboratory proficiency test program for the quantitation, pharmacokinetic modeling, and busulfan dosing in plasma was developed. Previous proficiency rounds (ie, the first 2) found that 67%-85% and 71%-88% of the dose recommendations were inaccurate, respectively.
METHODS
A proficiency test scheme was developed by the Dutch Foundation for Quality Assessment in Medical Laboratories (SKML) and consisted of 2 rounds per year, with each round containing 2 busulfan samples. In this study, 5 subsequent proficiency tests were evaluated. In each round, the participating laboratories reported their results for 2 proficiency samples (ie, low and high busulfan concentrations) and a theoretical case assessing their pharmacokinetic modeling and dose recommendations. Descriptive statistics were performed, with ±15% for busulfan concentrations and ±10% for busulfan plasma exposure. The dose recommendations were deemed accurate.
RESULTS
Since January 2020, 41 laboratories have participated in at least 1 round of this proficiency test. Over the 5 rounds, an average of 78% of the busulfan concentrations were accurate. Area under the concentration-time curve calculations were accurate in 75%-80% of the cases, whereas only 60%-69% of the dose recommendations were accurate. Compared with the first 2 proficiency test rounds (PMID 33675302, October, 2021), the busulfan quantitation results were similar, but the dose recommendations worsened. Some laboratories repeatedly submit results that deviated by more than 15% from the reference values.
CONCLUSIONS
The proficiency test showed persistent inaccuracies in busulfan quantitation, pharmacokinetic modeling, and dose recommendations. Additional educational efforts have yet to be implemented; regulatory efforts seem to be needed. The use of specialized busulfan pharmacokinetic laboratories or a sufficient performance in busulfan proficiency tests should be required for HCT centers that prescribe busulfan.
Topics: Humans; Busulfan; Hematopoietic Stem Cell Transplantation; Laboratory Proficiency Testing; Laboratories; Drug Monitoring; Transplantation Conditioning
PubMed: 37199431
DOI: 10.1097/FTD.0000000000001107 -
The Canadian Journal of Hospital... 2023Given altered pharmacokinetics in people with cystic fibrosis (pwCF), there is debate regarding optimal strategies for therapeutic drug monitoring (TDM) for...
BACKGROUND
Given altered pharmacokinetics in people with cystic fibrosis (pwCF), there is debate regarding optimal strategies for therapeutic drug monitoring (TDM) for aminoglycosides and vancomycin administered intravenously.
OBJECTIVES
To determine the TDM strategy for IV aminoglycosides and IV vancomycin associated with optimal clinical outcomes in pwCF.
DATA SOURCES
Several databases (MEDLINE, Embase, CINAHL, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov ) were searched from inception to November 15, 2020, with searches rerun on February 13, 2023.
STUDY SELECTION AND DATA EXTRACTION
Full articles evaluating TDM strategies and clinical outcomes in pwCF receiving IV aminoglycosides or IV vancomycin were included.
DATA SYNTHESIS
Three studies met the inclusion criteria for IV aminoglycosides, and 1 study met the inclusion criteria for IV vancomycin. Data are presented with descriptive analyses.
CONCLUSIONS
The available evidence is insufficient to determine an optimal TDM strategy for IV aminoglycoside or IV vancomycin therapy in pwCF.
PubMed: 37767394
DOI: 10.4212/cjhp.3429 -
Journal of Clinical Medicine Apr 2024Patients with cystic fibrosis (CF) commonly experience pulmonary exacerbations, and it is recommended by the TOPIC study to treat this with tobramycin at a dose of 10...
Patients with cystic fibrosis (CF) commonly experience pulmonary exacerbations, and it is recommended by the TOPIC study to treat this with tobramycin at a dose of 10 mg/kg once daily. The aim of this study was to evaluate the target attainment of the current dosing regimen. A single-center retrospective cohort study of child and adult patients with CF who received tobramycin between 2019 and 2022 was conducted. Descriptive statistics and linear mixed models were used to assess target attainment for tobramycin. In total, 25 patients (53 courses), of which 10 were children (12 courses) and 15 were adults (41 courses), were included. Those 25 patients all received 10 mg/kg/day. The tobramycin peak concentrations were supratherapeutic in 82.9% and therapeutic in 100.0% of adults and children, respectively. The trough concentrations were outside the target range in 0% and 5.1% of children and adults, respectively. We found lower tobramycin concentrations with the same dose in children compared to adults. This study illustrates the need to validate dosing advice in a real-world setting, as supratherapeutic concentrations of tobramycin were prevalent in adults with CF.
PubMed: 38731170
DOI: 10.3390/jcm13092641 -
BMC Pulmonary Medicine Jan 2024Despite global efforts to control the COVID-19 pandemic, the emergence of new viral strains continues to pose a significant threat. Accurate patient stratification,...
BACKGROUND
Despite global efforts to control the COVID-19 pandemic, the emergence of new viral strains continues to pose a significant threat. Accurate patient stratification, optimized resource allocation, and appropriate treatment are crucial in managing COVID-19 cases. To address this, a simple and accurate prognostic tool capable of rapidly identifying individuals at high risk of mortality is urgently needed. Early prognosis facilitates predicting treatment outcomes and enables effective patient management. The aim of this study was to develop an early predictive model for assessing mortality risk in hospitalized COVID-19 patients, utilizing baseline clinical factors.
METHODS
We conducted a descriptive cross-sectional study involving a cohort of 375 COVID-19 patients admitted and treated at the COVID-19 Patient Treatment Center in Military Hospital 175 from October 2021 to December 2022.
RESULTS
Among the 375 patients, 246 and 129 patients were categorized into the survival and mortality groups, respectively. Our findings revealed six clinical factors that demonstrated independent predictive value for mortality in COVID-19 patients. These factors included age greater than 50 years, presence of multiple underlying diseases, dyspnea, acute confusion, saturation of peripheral oxygen below 94%, and oxygen demand exceeding 5 L per minute. We integrated these factors to develop the Military Hospital 175 scale (MH175), a prognostic scale demonstrating significant discriminatory ability with an area under the curve (AUC) of 0.87. The optimal cutoff value for predicting mortality risk using the MH175 score was determined to be ≥ 3 points, resulting in a sensitivity of 96.1%, specificity of 63.4%, positive predictive value of 58%, and negative predictive value of 96.9%.
CONCLUSIONS
The MH175 scale demonstrated a robust predictive capacity for assessing mortality risk in patients with COVID-19. Implementation of the MH175 scale in clinical settings can aid in patient stratification and facilitate the application of appropriate treatment strategies, ultimately reducing the risk of death. Therefore, the utilization of the MH175 scale holds significant potential to improve clinical outcomes in COVID-19 patients.
TRIAL REGISTRATION
An independent ethics committee approved the study (Research Ethics Committee of Military Hospital 175 (No. 3598GCN-HDDD; date: October 8, 2021), which was performed in accordance with the Declaration of Helsinki, Guidelines for Good Clinical Practice.
Topics: Humans; Middle Aged; COVID-19; Cross-Sectional Studies; Pandemics; Patients; Area Under Curve
PubMed: 38200490
DOI: 10.1186/s12890-023-02838-1