ORCID Profile
0000-0002-4182-065X
Current Organisation
University of Sharjah
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 08-2021
Publisher: MDPI AG
Date: 30-12-2022
Abstract: Background: Coronavirus disease 2019 (COVID-19) caused significant mortality and mortality worldwide. There is limited information describing the outcomes of COVID-19 in cancer patients. Methods: We utilized the Healthcare Cost and Utilization Project Nationwide Inpatient S le (NIS) 2020 database to collect information on cancer patients hospitalized for COVID-19 in the United States. Using the International Classification of Diseases, 10th revision, Clinical Modification (ICD-10-CM) coding system, adult (≥18 years) patients with COVID-19 were identified. Adjusted analyses were performed to assess for mortality, morbidity, and resource utilization among cancer patients. Results: A total of 1,050,045 patients were included. Of them, 27,760 had underlying cancer. Cancer patients were older and had more comorbidities. The all-cause in-hospital mortality rate in cancer patients was 17.58% vs. 11% in non-cancer. After adjusted logistic regression, cancer patients had a 21% increase in the odds of all-cause in-hospital mortality compared with those without cancer (adjusted odds ratio (aOR) 1.21, 95%CI 1.12–1.31, p-value 0.001). Additionally, an increased odds in acute respiratory failure rate was found (aOR 1.14, 95%CI 1.06–1.22, p-value 0.001). However, no significant differences were found in the odds of septic shock, acute respiratory distress syndrome, and mechanical ventilation between the two groups. Additionally, no significant differences in the mean length of hospital stay and the total hospitalization charges between cancer and non-cancer patients. Conclusion: Cancer patients hospitalized for COVID-19 had increased odds of all-cause in hospital mortality and acute respiratory failure compared with non-cancer patients.
Publisher: Informa UK Limited
Date: 17-04-2020
Publisher: MDPI AG
Date: 10-01-2023
DOI: 10.3390/IJMS24021354
Abstract: Untargeted multi-omics analysis of plasma is an emerging tool for the identification of novel biomarkers for evaluating disease prognosis, and for developing a better understanding of molecular mechanisms underlying human disease. The successful application of metabolomic and proteomic approaches relies on reproducibly quantifying a wide range of metabolites and proteins. Herein, we report the results of untargeted metabolomic and proteomic analyses from blood plasma s les following analyte extraction by two frequently-used solvent systems: chloroform/methanol and methanol-only. Whole blood s les were collected from participants (n = 6) at University Hospital Sharjah (UHS) hospital, then plasma was separated and extracted by two methods: (i) methanol precipitation and (ii) 4:3 methanol:chloroform extraction. The coverage and reproducibility of the two methods were assessed by ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS). The study revealed that metabolite extraction by methanol-only showed greater reproducibility for both metabolomic and proteomic quantifications than did methanol/chloroform, while yielding similar peptide coverage. However, coverage of extracted metabolites was higher with the methanol/chloroform precipitation.
Publisher: Wiley
Date: 09-06-2022
DOI: 10.1002/CPT.2640
Abstract: We aimed to develop population pharmacokinetic harmacodynamic (PK/PD) models that can effectively describe ketamine and norketamine PK/PD relationships for Montgomery–Åsberg Depression Rating Scale (MADRS) scores, blood pressure (BP), and heart rate (HR) following i.v., s.c., and i.m. ketamine administration in patients with treatment‐refractory depression. Ketamine PK/PD data were collected from 21 treatment‐refractory depressed participants who received ketamine (dose titration 0.1–0.5 mg/kg as single doses) by i.v., s.c., or i.m. administration. Model development used nonlinear mixed effect modeling. Ketamine and norketamine PK were best described using two‐compartment models with first‐order absorption after s.c. and i.m. administration. Estimated ketamine bioavailability after i.m. and s.c. was ~ 64% with indistinguishable first‐order absorption rate constants. Allometric scaling of body weight on all clearance and volumes of distribution improved the model fit. The delay in the concentration‐response relationship for MADRS scores was best described using a turnover model (turnover time ~ 42 hours), whereas for the BP and HR rates this was an immediate effect model. For all PD effects, ketamine alone was superior to models with norketamine concentration linked to an effect. No covariates were identified for PD effects. The estimated half‐maximal effective concentration from the MADRS score, BP, and HR were 0.44, 468, and 7,580 ng/mL, respectively. The integrated population models were able to effectively describe the PK/PD relationships for MADRS scores, BP, and HR after i.v., s.c., and i.m. ketamine administration. These findings allow for a deeper understanding of the complex relationships between route of ketamine administration and clinical response and safety.
Publisher: Wiley
Date: 28-07-2022
DOI: 10.1111/BCP.15462
Abstract: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. Blood s les (n = 239) were collected using sparse and rich s ling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high‐performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. The time course of the plasma concentrations of febuxostat is best described by a two‐compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h −1 , 32.8 l, 19.4 l, 3.6 h −1 and 1.25 l h −1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.
Publisher: AME Publishing Company
Date: 03-2022
DOI: 10.21037/TLCR-21-938
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0BM01355B
Abstract: 3D printing is introduced as rapid and facile approach to prepare personalized drug-eluting stents for the treatment of oesophageal cancers.
Publisher: Veterinary World
Date: 04-2023
DOI: 10.14202/VETWORLD.2023.693-703
Abstract: Background and Aim: Human monkeypox is an emerging global threat. Hundreds of publications were disseminated in the last few months. This study aimed to map, analyze, and evaluate the bibliometric indicators of the global monkeypox research output. Materials and Methods: All documents published in the past 20 years were retrieved using the Scopus database. Papers published in English and peer-reviewed journals were included. VOSviewer was used to create density and network visualization maps. Results: A total of 1725 published documents were retrieved. Of these, 53% were published in 2022. The average number of authors per document was 4.2. Authors from the USA were the most active and published about 42.1% of the total documents. International collaboration was evident between the USA and both UK and Congo. Keywords mapping identified the main research lines in this field that correlate monkeypox with public health, smallpox, vaccination, and antiviral treatment. Conclusion: This study analyzed and mapped the expanding field of monkeypox research across the world. The bibliometric analysis revealed that the United States has contributed greatly in terms of both in idual researchers and academic institutions. There was less cooperation on a global scale than was anticipated. Fostering international cooperation is essential for countering this worldwide danger. Additional scientific research should be conducted to investigate the link between smallpox immunization and monkeypox epidemics. Keywords: bibliometric study, coronavirus disease, epidemic, monkeypox, outbreak, smallpox, virus.
Publisher: Pharmaceutical Society of Japan
Date: 2011
DOI: 10.1248/CPB.59.155
Abstract: The aim of this study was to evaluate the influence of Na-bicarbonate as an effervescent agent on the floating and sustained-release characteristics in 0.1 M HCl of tablets made of Eudragit E PO (EE) and/or Eudragit L-100-55 (EL) as matrix formers at different EE:EL weight ratios: 0:100, 25:75, 50:50, 75:25, and 100:0. The tablets were made by direct compression utilizing metronidazole as a model drug. Effervescent tablets with 50EE/50EL (w/w) showed the best floating and sustained drug release properties in the dissolution medium. The corresponding noneffervescent tablets were nonfloating and showed significantly faster drug release. Effervescent tablets with single polymers showed an immediate drug release pattern. These results were explained by Fourier-transform infrared spectroscopy and elemental analysis, which showed strong evidence of interpolyelectrolyte complexation between EE and EL when they were exposed to 0.1 M HCl as an effervescent hybrid matrix, but not as a noneffervescent hybrid matrix. The role of Na-bicarbonate in allowing EE-EL complexation during dissolution was explained as due to raising the pH around EL particles for sufficient polymer ionization and ionic-interaction with the ionized EE.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2021
DOI: 10.1007/S13346-020-00853-X
Abstract: Simvastatin (SIM) is a commonly used cholesterol-lowering drug that can reduce the risk of major cardiovascular events. However, due to its poor intrinsic water solubility, the drug is poorly absorbed from the gastrointestinal tract and exhibits a low oral bioavailability of approximately 5%. The aim of this study was to fabricate and optimize SIM encapsulated silica-lipid hybrids (SLH) as a solid-state lipid-based formulation to enhance absorption and bioavailability during a human in vivo pharmacokinetic study. SLH formulations were formulated by spray drying a submicron emulsion with either Aerosil® 300 fumed silica nanoparticles (SLH-A) or Syloid® 244 amorphous micronized silica (SLH-B). A cross-over, double-blinded study design was implemented to evaluate the performance of SLH formulations compared with a commercially available formulation in 12 healthy male participants after oral administration under fasting conditions. SLH formulations enhanced the bioavailability of SIM up to 1.6-fold and more importantly the active simvastatin acid (SIMA), 3.5-fold when compared with an equivalent dose of commercial formulation. The results demonstrate that the porous nanostructure of SLH impact systemic SIM and SIMA concentrations and may serve as a novel approach to enhance the bioavailability of specifically the parent or metabolite. No significant difference was observed in exposure when SLH formulations were administered at 10 mg in comparison with 20 mg of the commercial formulation, suggesting the potential for dose reduction. The study indicated that SLH formulations were safe and well-tolerated when administered to healthy males, confirming the commercial potential of SLH to enhance the bioavailability of poorly water-soluble drugs. Graphical abstract.
Publisher: Wiley
Date: 23-08-2016
DOI: 10.1111/PAN.12995
Abstract: Physiologically-based pharmacokinetic (PBPK) models represent drug kinetics in one or more 'real' organs (and hence require submodels of organs/tissues) and they describe 'whole-body' kinetics by joining together submodels with drug transport by blood flow as dictated by anatomy. They attempt to reproduce 'measureable' physiological and/or pharmacokinetic processes rather than more abstract rate constants and volumes. PBPK models may be built using a 'bottom-up' approach, where parameters are chosen from first principles, literature, or in vitro data as opposed to a 'top-down' approach, where all parameters are estimated from data. The basic principles of PBPK models are described, focusing on the equations for three in idual organs: a single flow-limited compartment describing distribution only, a membrane-limited compartment describing distribution, and a single flow-limited compartment with elimination. These organ models are linked to make a basic three-compartment physiological model of the whole body. PBPK models are particularly suited to scaling kinetics across body size (e.g., adult to neonate) and species (e.g., animal to first-in-man) as physiology and pharmacology can be represented by independent parameters. Maturation models can be incorporated as for compartmental models. PBPK models are now available in commercial software packages, and are perhaps now more accessible than ever. Alternatively, even complex PBPK models can be represented in generic differential equation-solving software using the simple principles described here. The relative ease of constructing the code for PBPK models belies the most difficult aspect of their implementation-collecting, collating, and justifying the data used to parameterize the model.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.VASCN.2015.03.004
Abstract: The analytical solutions to compartmental pharmacokinetic models are well known, but have not been presented in a form that easily allows for complex dosing regimen and changes in covariate arameter values that may occur at discrete times within and/or between dosing intervals. Laplace transforms were used to derive ADVAN-style analytical solutions for 1, 2, and 3 compartment pharmacokinetic linear models of intravenous and first-order absorption drug administration. The equations calculate the change in drug amounts in each compartment of the model over a time interval (t t = t2 - t1) accounting for any dose or covariate events acting in the time interval. The equations were coded in the R language and used to simulate the time-course of drug amounts in each compartment of the systems. The equations were validated against commercial software [NONMEM (Beal, Sheiner, Boeckmann, & Bauer, 2009)] output to assess their capability to handle both complex dosage regimens and the effect of changes in covariate arameter values that may occur at discrete times within or between dosing intervals. For all tested pharmacokinetic models, the time-course of drug amounts using the ADVAN-style analytical solutions were identical to NONMEM outputs to at least four significant figures, confirming the validity of the presented equations. To our knowledge, this paper presents the ADVAN-style equations for common pharmacokinetic models in the literature for the first time. The presented ADVAN-style equations overcome obstacles to implementing the classical analytical solutions in software, and have speed advantages over solutions using differential equation solvers. The equations presented in this paper fill a gap in the pharmacokinetic literature, and it is expected that these equations will facilitate the investigation of useful open-source software for modelling pharmacokinetic data.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2019
DOI: 10.1007/S13318-018-0519-1
Abstract: SUBA-itraconazole and Sporanox are two oral formulations of itraconazole. Drug-drug interactions with omeprazole have been previously reported however, mechanistic understanding of the pharmacological and physiological interactions of omeprazole with orally administered itraconazole within a population modeling paradigm is lacking. The objective of this analysis was to mechanistically describe and quantify the effect of omeprazole on the pharmacokinetics of itraconazole and its major metabolite, hydroxyitraconazole from the SUBA itraconazole and Sporanox formulations. An in vitro-in vivo (IVIV) pharmacokinetic model of itraconazole and hydroxyitraconazole was developed including data from an omeprazole interaction study with SUBA itraconazole. Meta-models of gastric pH for healthy subjects and subjects receiving omeprazole were integrated into the IVIV model to capture omeprazole-mediated gastric pH changes on itraconazole dissolution and absorption. Omeprazole influenced the kinetics of itraconazole through altering the dissolution and absorption due to the pH-dependent solubility of itraconazole, inhibition of efflux transporters, and inhibiting the metabolism of itraconazole and hydroxyitraconazole. The model-predicted population effects of omeprazole on itraconazole from SUBA-itraconazole were to increase the area under the concentration-time curve (AUC Unlike SUBA itraconazole, which requires basic pH for itraconazole release, the omeprazole-induced pH-mediated reduction in Sporanox dissolution overrides any increased exposure from the drug-drug interaction at hepatic metabolizing enzymes or efflux transporters. The model presented here is the most complete quantitative description of the pharmacokinetics of itraconazole and hydroxyitraconazole currently available.
Publisher: SAGE Publications
Date: 2021
DOI: 10.1177/1759720X211009020
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with increased risk of cardiovascular disease (CVD). Treatment for CVD may involve pharmacological agents that antagonise beta adrenergic receptors. These receptors may play an important role in immunology, and the effects of beta-blockers (BB) in RA is unknown. The aim of this study was to investigate the association between BB use and remission in patients with RA initiating tocilizumab +/− conventional synthetic (cs-) DMARD therapy. Data was pooled from five randomised trials investigating tocilizumab and/or csDMARD treatment in RA (primarily methotrexate). The association between BB use and remission according to the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) was assessed by Cox proportional hazard analysis. Sensitivity analysis in patients with pre-existing CVD and an exploratory analysis of the impact of other CVD drugs were conducted. Data were available from 5502 participants, 594 (10.8%) of whom were using systemic BB. BB use was associated with less frequent SDAI remission in the total [adjusted hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.57–0.87, p = 0.001] and CVD cohort [adjusted HR 0.72 (0.57–0.90, p = 0.005)]. The association was consistent between trials (interaction p = 0.44) and treatment arms (interaction p = 0.06). No significant association between remission and β1-receptor selectivity was identified ( p = 0.16), and the association was independent from other cardiovascular drug use. Similar associations between BB use and CDAI remission were observed. In a large, pooled cohort of RA patients initiating csDMARDs and/or tocilizumab, BB use was independently associated with less frequent remission.
Publisher: MDPI AG
Date: 25-12-2022
DOI: 10.3390/IJMS24010348
Abstract: Glioblastoma (GB) is a primary malignancy of the central nervous system that is classified by the WHO as a grade IV astrocytoma. Despite decades of research, several aspects about the biology of GB are still unclear. Its pathogenesis and resistance mechanisms are poorly understood, and methods to optimize patient diagnosis and prognosis remain a bottle neck owing to the heterogeneity of the malignancy. The field of omics has recently gained traction, as it can aid in understanding the dynamic spatiotemporal regulatory network of enzymes and metabolites that allows cancer cells to adjust to their surroundings to promote tumor development. In combination with other omics techniques, proteomic and metabolomic investigations, which are a potent means for examining a variety of metabolic enzymes as well as intermediate metabolites, might offer crucial information in this area. Therefore, this review intends to stress the major contribution these tools have made in GB clinical and preclinical research and highlights the crucial impacts made by the integrative “omics” approach in reducing some of the therapeutic challenges associated with GB research and treatment. Thus, our study can purvey the use of these powerful tools in research by serving as a hub that particularly summarizes studies employing metabolomics and proteomics in the realm of GB diagnosis, treatment, and prognosis.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2016
DOI: 10.1007/S11095-016-1917-1
Abstract: To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption. IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM. Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a 'Shiny' application. An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.
Publisher: Frontiers Media SA
Date: 05-08-2021
Publisher: Hamad bin Khalifa University Press (HBKU Press)
Date: 2012
Abstract: Objectives: To investigate the synthesis and in vitro characterization of a novel family of photo-cross-linked biodegradable poly(alkylene-co-tartrate) (PAT) for the purpose of their use in implantable drug delivery and tissue engineering applications. Methods: PAT prepolymers were first synthesized via polycondensation reaction of L-tartaric acid with alkylene diols of varying chain lengths (C6-C12) at 130°C for two hours under nitrogen atmosphere followed by one extra hour under vacuum to form PAT prepolymers. The purified prepolymers were then acrylated using an equimolar ratio of acryloyl chloride and triethylamine. Following purification, the acrylated poly(alkylene tartrate) prepolymers (APAT) of varying degrees of acrylation were photo-cross-linked to form the elastomers. The prepared prepolymers were characterized using Proton Nuclear Magnetic Resonance (1H-NMR), Fourier transform infrared (FTIR) analysis and differential scanning calorimetry (DSC). The PAT elastomers were also subjected to sol-gel content analysis and mechanical testing. The osmotic-driven release of protein drug from those elastomers was also investigated. Results: 1H-NMR and FTIR analysis confirmed the chemical structure and the purity of the PAT prepolymers and confirmed the existence of the acryloyl moieties at the formed chains terminals. Osmotic driven release from PAT elastomeric matrices was found to be controlled by changing the osmotic activity of the loaded drug mix as well as the degree of macromers acrylation, without altering the release kinetics. The obtained photo-cross-linked elastomers were stretchable and rubbery and swell rather than dissolve in most of organic solvents. Mechanical properties were found to be dependent on the number of methylene groups in the chain of precursor diol and the crosslinking density of the elastomeric matrices. Conclusions: Biodegradable, polyester matrices were successfully prepared and characterized. The family of PAT biodegradable polyesters has promising use in drug delivery and other biomedical applications including tissue engineering.
Publisher: Hamad bin Khalifa University Press (HBKU Press)
Date: 2012
Abstract: Objectives: To formulate and evaluate oral dosage forms of metformin hydrochloride (MH) having sustained-release properties that would also increase MH bioavailability and address the shortcomings in the currently marketed sustained-release tablets. Methods: MH micronized powder was dispersed in molten polymeric matrices composed of Gelucire® 50/13 and various proportions of high molecular weight hydrophilic polymers, hydrophobic oily semisolid excipients, and mucoadhesive polymeric materials. The MH loaded matrices were filled in hard gelatin capsules (HGC) each containing 500 mg MH and were subsequently characterized using differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. The prepared HGC were subjected to content uniformity and in vitro dissolution testing according to the USP-35 compendium requirements. The dissolution data were compared to instant and sustained-release marketed tablets. The effect of incorporating various proportions of the semisolid excipients on MH dissolution release rate, were also investigated. Results: MH content of the prepared HGC ranged between 96 to 103%. All the prepared semisolid filled HGC resulted in extended-release profiles of MH that lasted between 5 to 11 hours and demonstrated a release pattern which typically follows the release from mixes of triglycerides with polyethylene glycol esters of fatty acids. The incorporation of mucoadhesive excipients like carbomer to the Gelucire® 50/13-MH semisolid matrices extended the release of MH from 5 hours initially to 9 hours as a result of the formation of a gel layer around the matrix. However, the incorporation of different hydrophilic excipients like PEG35000 and Gelucire® 44/14 along with the mucoadhesive excipients sustained the release of MH up to 11 hours. XRD analysis of the MH prepared matrices demonstrated minor changes in the crystalline nature of MH. Depending on the loading ratios and the nature of the semisolid matrices used, DSC analysis revealed the changes in MH crystallinity to be from 100 to 23%. Conclusion: HGC formulated using semisolid matrices showed promising results in extending the release of MH. However, bioavailability studies to test the ability of such Gelucire based HGC of MH to improve its bioavailability and in vivo residence times are future plans.
Publisher: MDPI AG
Date: 21-04-2021
Abstract: Machine learning (ML) may enhance the efficiency of developing accurate prediction models for survival, which is critical in informing disease prognosis and care planning. This study aimed to develop an ML prediction model for survival outcomes in patients with urothelial cancer-initiating atezolizumab and to compare model performances when built using an expert-selected (curated) versus an all-in list (uncurated) of variables. Gradient-boosted machine (GBM), random forest, Cox-boosted, and penalised, generalised linear models (GLM) were evaluated for predicting overall survival (OS) and progression-free survival (PFS) outcomes. C-statistic (c) was utilised to evaluate model performance. The atezolizumab cohort in IMvigor210 was used for model training, and IMvigor211 was used for external model validation. The curated list consisted of 23 pretreatment factors, while the all-in list consisted of 75. Using the best-performing model, patients were stratified into risk tertiles. Kaplan–Meier analysis was used to estimate survival probabilities. On external validation, the curated list GBM model provided slightly higher OS discrimination (c = 0.71) than that of the random forest (c = 0.70), CoxBoost (c = 0.70), and GLM (c = 0.69) models. All models were equivalent in predicting PFS (c = 0.62). Expansion to the uncurated list was associated with worse OS discrimination (GBM c = 0.70 random forest c = 0.69 CoxBoost c = 0.69, and GLM c = 0.69). In the atezolizumab IMvigor211 cohort, the curated list GBM model discriminated 1-year OS probabilities for the low-, intermediate-, and high-risk groups at 66%, 40%, and 12%, respectively. The ML model discriminated urothelial-cancer patients with distinctly different survival risks, with the GBM applied to a curated list attaining the highest performance. Expansion to an all-in approach may harm model performance.
Publisher: Springer Science and Business Media LLC
Date: 29-10-2020
DOI: 10.1038/S41598-020-75673-7
Abstract: The aim of this study was to investigate the association between body-mass index (BMI) and remission in RA patients receiving conventional synthetic (cs-) or the biological Disease-Modifying Antirheumatic Drug (DMARD), tocilizumab. In idual participant data (IPD) were pooled from five trials investigating tocilizumab and/or csDMARDs therapy (primarily methotrexate) for RA. Time to first remission was recorded according to the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI). BMI was classified according to WHO definitions. Associations between baseline BMI and remission were assessed by Cox-proportional hazard analysis. IPD were available from 5428 patients treated with tocilizumab ± csDMARDs (n = 4098) or csDMARDs alone (n = 1330). Of these, 1839 (33.9%) had normal BMI, 1780 (32.8%) overweight, 1652 (30.4%) obese and 157 (2.9%) were underweight. Obesity, compared to normal BMI, was associated with less frequent remission using SDAI (adjusted HR 0.80 [95% CI 0.70–0.92]) and CDAI (adjusted HR 0.77 [0.68–0.87]). As continuous variable, increased BMI was associated with less frequent SDAI (P = 0.001) and CDAI (P = 0.001) defined remission. No heterogeneity in identified associations was observed between studies (P = 0.08) or treatments (P = 0.22). Obesity was negatively associated with RA disease remission regardless of RA therapy, suggesting that baseline BMI should be considered as a stratification factor in future RA trials.
Publisher: MDPI AG
Date: 27-07-2021
Abstract: We thank Auclin et al. [...]
Publisher: Springer Science and Business Media LLC
Date: 17-11-2018
DOI: 10.1007/S10928-017-9555-8
Abstract: The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development. Model development was conducted in NONMEM in a stepwise manner. First, a model of intravenous data (systemic kinetics) was established and then extended to include the oral data. The latter was then extended to establish the in vitro-in vivo pharmacokinetic model. The systemic disposition of ICZ was best described by a 3-compartment model with oral absorption described by 4-transit compartments and HICZ distribution by a 1-compartment model. ICZ clearance was best described using a mixed inhibition model that allowed HICZ concentrations to inhibit the clearance of parent drug. HICZ clearance was described by Michaelis-Menten elimination kinetics. An in vitro-in vivo model was successfully established for both formulations. The presented model was able to describe ICZ and HICZ plasma concentrations over a wide range of oral and intravenous doses and allowed the exploration of complexities associated with the non-linear ICZ and HICZ kinetics. The model may provide insight into the variability in exposure of ICZ with respect to relating in vivo dissolution characteristics with in vivo disposition kinetics.
Publisher: SAGE Publications
Date: 2022
DOI: 10.1177/1759720X221111613
Abstract: Rheumatoid arthritis (RA) is an inflammatory autoimmune condition associated with an increased risk of developing depression and anxiety. Depression and anxiety are associated with worse outcomes in RA, but the magnitude of the effect of each condition on RA outcomes is unclear. It is also unknown how pharmacological treatment of depression affects RA outcomes. The primary aim of this study was to investigate the association of comorbid depression and anxiety with remission in patients with RA. Secondary aims were to determine the association between comorbid depression and anxiety on patient-reported outcomes and the relationship between concomitant use of antidepressants and remission in patients with depression. Data from patients with moderate to severe RA were pooled from five randomised controlled trials investigating tocilizumab and conventional synthetic disease-modifying agents. Remission was defined as a clinical disease activity index (CDAI) of ⩽2.8 and simple disease activity index (SDAI) of ⩽3.3. The association between the time to reach remission and depression and anxiety was analysed using Cox proportional hazard analysis. In idual patient data were available from 5502 subjects, of whom 511 had depression, 236 had anxiety and 387 were using antidepressants. Depression was significantly associated with reduced remission [adjusted HR (95% CI): 0.62 (0.48–0.80), p 0.001 and adjusted HR (95% CI): 0.59 (0.44–0.79), p 0.001] using CDAI and SDAI, respectively. Depression was associated with a lower likelihood of achieving more subjective outcomes (⩽1 physician global assessment, ⩽1 patient global assessment) and ⩽1 28-swollen joint count, but not ⩽1 28-tender joint count or C-reactive protein measurement. Treatment with antidepressants did not improve outcomes for patients with depression. Anxiety was not significantly associated with RA remission. Comorbid depression, but not anxiety, was associated with less frequent remission. Concomitant antidepressant use was not associated with improvements in RA outcomes in patients with depression.
Publisher: Wiley
Date: 27-07-2021
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EJPB.2016.11.034
Abstract: This article reviews the major physiological and physicochemical principles of the effect of food and gastrointestinal (GI) pH on the absorption and bioavailability of oral drugs, and the various absorption models that are used to describe redict oral drug absorption. The rate and extent of oral drug absorption is determined by a complex interaction between a drug's physicochemical properties, GI physiologic factors, and the nature of the formulation administered. GI pH is an important factor that can markedly affect oral drug absorption and bioavailability as it may have significant influence on drug dissolution & solubility, drug release, drug stability, and intestinal permeability. Different regions of the GI tract have different drug absorptive properties. Thus, the transit time in each GI region and its variability between subjects may contribute to the variability in the rate and/or extent of drug absorption. Food-drug interactions can result in delayed, decreased, increased, and sometimes un-altered drug absorption. Food effects on oral absorption can be achieved by direct and indirect mechanisms. Various models have been proposed to describe oral absorption ranging from empirical models to the more sophisticated "mechanism-based" models. Through understanding of the physicochemical and physiological rate-limiting factors affecting oral absorption, modellers can implement simplified population-based modelling approaches that are less complex than whole-body physiologically-based models but still capture the essential elements in a physiological way and hence will be more suited for population modelling of large clinical data sets. It will also help formulation scientists to better predict formulation performance and to develop formulations that maximize oral bioavailability.
Publisher: Wiley
Date: 12-07-2021
DOI: 10.1111/BCPT.13634
Abstract: The physiological changes following Roux‐en‐Y gastric bypass (RYGB) surgery may impact drug release from mechanistically different controlled‐release tablets, making generic substitution inappropriate. This study aimed to characterise the pharmacokinetic‐pharmacodynamic relationships of oxycodone from a lipid‐based and water‐swellable controlled‐release tablet in RYGB patients. Twenty RYGB patients received 10‐mg oral solution oxycodone or 20‐mg controlled‐release (water‐swellable or lipid‐based) oxycodone in a three‐way, randomised, semiblinded and cross‐over study. Blood s ling and pupillary recordings were conducted over a 24‐h period. A previously established pharmacokinetic‐pharmacodynamic model of these three formulations in healthy volunteers was used in the analysis as a reference model. No differences in absorption kinetics were seen between controlled‐release formulations in patients. However, the absorption lag time was 11.5 min in patients vs 14 min in healthy volunteers for controlled‐release tablets ( P 0.001). Furthermore, oral bioavailability was 14.4% higher in patients compared to healthy volunteers regardless of formulation type ( P 0.001). Oxycodone pharmacodynamics were not significantly affected by formulation or patient status. However, baseline pupil diameter was inversely correlated with age ( P 0.001) and plasma concentrations of oxycodone at half‐maximum effect were 31% lower in males compared to females ( P 0.05). Generic substitution of monophasic lipid‐based and water‐swellable controlled‐release oxycodone tablets may be considered safe in RYGB patients.
Publisher: Springer Science and Business Media LLC
Date: 20-07-2016
DOI: 10.1208/S12248-016-9953-7
Abstract: This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) transit times of non-disintegrating single-unit ("tablet") and multiple-unit ("pellets/multi-unit tablet") solid dosage forms, characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of the distributions of GI transit times in the respective GI regions to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, gastric, small intestinal and colonic transit times under fed and fasted conditions. Meta-analysis used the "metafor" package of the R language. Meta-models of GI transit were assumed to be log-normally distributed between the studied populations. Twenty-nine studies including 125 reported means and standard deviations were used in the meta-analysis. Caloric content of administered food increased variability and delayed the gastric transit of both pellets and tablets. Conversely, food caloric content reduced the variability but had no significant influence on the mean small intestinal transit time (SITT). Food had no significant effect on the transit time through the colon. The transit of pellets through the colon was significantly slower than that of single-unit tablets which is most likely related to their smaller size. GI transit times may influence the dissolution and absorption of oral drugs. The meta-models of GI transit times may be used as part of semi-physiological absorption models to characterize the influence of transit time on the dissolution, absorption and in vivo pharmacokinetic profiles of oral drugs.
Publisher: Springer Science and Business Media LLC
Date: 05-08-2016
DOI: 10.1208/S12248-016-9952-8
Abstract: This study aimed to conduct a quantitative meta-analysis for the values of, and variability in, gastrointestinal (GI) pH in the different GI segments characterize the effect of food on the values and variability in these parameters and present quantitative meta-models of distributions of GI pH to help inform models of oral drug absorption. The literature was systemically reviewed for the values of, and the variability in, GI pH under fed and fasted conditions. The GI tract was categorized into the following 10 distinct regions: stomach (proximal, mid-distal), duodenum (proximal, mid-distal), jejunum and ileum (proximal, mid, and distal small intestine), and colon (ascending, transverse, and descending colon). Meta-analysis used the "metafor" package of the R language. The time course of postprandial stomach pH was modeled using NONMEM. Food significantly influenced the estimated meta-mean stomach and duodenal pH but had no significant influence on small intestinal and colonic pH. The time course of postprandial pH was described using an exponential model. Increased meal caloric content increased the extent and duration of postprandial gastric pH buffering. The different parts of the small intestine had significantly different pH. Colonic pH was significantly different for descending but not for ascending and transverse colon. Knowledge of GI pH is important for the formulation design of the pH-dependent dosage forms and in understanding the dissolution and absorption of orally administered drugs. The meta-models of GI pH may also be used as part of semi-physiological pharmacokinetic models to characterize the effect of GI pH on the in vivo drug release and pharmacokinetics.
Publisher: MDPI AG
Date: 09-03-2021
Abstract: The lung immune prognostic index (LIPI) is proposed to differentiate prognosis and treatment benefit from immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC). There is minimal information on the predictive importance with first-line, combination ICI approaches. In post-hoc analysis of IMpower150, Cox-proportional hazard analysis assessed the association between LIPI groups and overall survival (OS) rogression free survival (PFS). IMpower150 involved chemotherapy-naïve, metastatic non-squamous NSCLC participants randomized atezolizumab-carboplatin-paclitaxel (ACP), bevacizumab-carboplatin-paclitaxel (BCP), or atezolizumab-BCP (ABCP). Good (0 factors), intermediate (1 factor), and poor LIPI (2 factors) were defined via derived neutrophil-to-lymphocyte ratio , and lactate dehydrogenase upper limit of normal. Of 1148 participants, 548 had good, 479 intermediate, and 121 poor LIPI. In 385 participants randomised ABCP, a significant association between LIPI and OS (HR (95%CI): intermediate LIPI = 2.16 (1.47–3.18), poor LIPI = 5.28 (3.20–8.69), p 0.001) and PFS (HR (95%CI): intermediate LIPI = 1.47 (1.11–1.95), poor LIPI = 3.02 (2.03–4.50), p 0.001) was identified. Median OS was 24, 16, and 7 months for good, intermediate, and poor LIPI, respectively. ACP associations were similar. Relative OS treatment effect (HR 95%CI) of ABCP vs. BCP was 0.78 (0.53–1.15), 0.67 (0.49–0.91), and 0.87 (0.51–1.47) for the good, intermediate, and poor LIPI groups, respectively (P(interaction) = 0.66), with no benefit in median OS observed in the poor LIPI group. LIPI identified subgroups with significantly different survival following ABCP and ACP initiation for chemotherapy-naïve, metastatic non-squamous NSCLC. There was insufficient evidence that LIPI identifies patients unlikely to benefit from ABCP treatment.
Publisher: Wiley
Date: 28-10-2019
DOI: 10.1111/BCPT.13330
Abstract: Oral controlled-release formulations are playing an ever-increasing role in opioid therapy however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (k
Publisher: MDPI AG
Date: 13-01-2023
DOI: 10.3390/IJMS24021604
Abstract: Skin cancer, including malignant melanoma (MM) and keratinocyte carcinoma (KC), historically named non-melanoma skin cancers (NMSC), represents the most common type of cancer among the white skin population. Despite decades of clinical research, the incidence rate of melanoma is increasing globally. Therefore, a better understanding of disease pathogenesis and resistance mechanisms is considered vital to accomplish early diagnosis and satisfactory control. The “Omics” field has recently gained attention, as it can help in identifying and exploring metabolites and metabolic pathways that assist cancer cells in proliferation, which can be further utilized to improve the diagnosis and treatment of skin cancer. Although skin tissues contain erse metabolic enzymes, it remains challenging to fully characterize these metabolites. Metabolomics is a powerful omics technique that allows us to measure and compare a vast array of metabolites in a biological s le. This technology enables us to study the dermal metabolic effects and get a clear explanation of the pathogenesis of skin diseases. The purpose of this literature review is to illustrate how metabolomics technology can be used to evaluate the metabolic profile of human skin cancer, using a variety of analytical platforms including gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). Data collection has not been based on any analytical method.
Publisher: Springer Science and Business Media LLC
Date: 28-02-2022
DOI: 10.1007/S00280-022-04411-9
Abstract: Sorafenib is an effective therapy for advanced hepatocellular carcinoma (HCC). Hand–foot syndrome (HFS) is a serious adverse effect associated with sorafenib therapy. This study aimed to develop an updated clinical prediction tool that allows personalized prediction of HFS following sorafenib initiation. In idual participant data from Phase III clinical trial NCT00699374 were used in Cox proportional hazard analysis of the association between pre-treatment clinicopathological data and grade ≥ 3 HFS occurring within the first 365 days of sorafenib treatment for advanced HCC. Multivariable prediction models were developed using stepwise forward inclusion and backward deletion and internally validated using a random forest machine learning approach. Of 542 patients, 116 (21%) experienced grades ≥ 3 HFS. The prediction tool was optimally defined by sex (male vs female), haemoglobin ( 130 vs ≥ 130 g/L) and bilirubin ( 10 vs 10–20 vs ≥ 20 µmol/L). The prediction tool was able to discriminate subgroups with significantly different risks of grade ≥ 3 HFS ( P ≤ 0.001). The high (score = 3 +)-, intermediate (score = 2)- and low (score = 0–1)-risk subgroups had 40%, 27% and 14% probability of developing grade ≥ 3 HFS within the first 365 days of sorafenib treatment, respectively. A clinical prediction tool defined by female sex, high haemoglobin and low bilirubin had high discrimination for predicting HFS risk. The tool may enable improved evaluation of personalized risks of HFS for patients with advanced HCC initiating sorafenib.
Publisher: Frontiers Media SA
Date: 08-2022
Abstract: Immune checkpoint inhibitors (ICIs) is the main treatment option for patients with metastatic renal cell carcinoma (mRCC) however, significant heterogeneity in response is commonly observed. This study aimed to evaluate the ability of C-reactive protein (CRP) to predict overall survival (OS) and progression-free survival (PFS) in patients with mRCC treated with immunotherapy. Data from patients with mRCC treated with atezolizumab plus bevacizumab in the IMmotion150 and IMmotion151 trials were pooled. Cox proportional regression was used to model prognostic associations. The relative importance of CRP against International Metastatic RCC Database Consortium (IMDC) factors was confirmed using machine learning. CRPs were available from 527 patients (mean[range] CRP, 6.3[0.21–340]mg/L). Elevated CRP was significantly associated with worse OS (HR[95%CI], 1.71[1.54–1.90], p& .001) and PFS (1.27[1.18–1.35], p& .001). CRP was the most prognostic factor for survival within the available clinicopathological data. The prognostic performance of CRP was superior to IMDC model for OS (CRP c=0.76, IMDC c=0.67, p& .001) and PFS (CRP OS c=0.62, IMDC c=0.59, p=0.03). Predicted 2-year OS probabilities for patients with CRP values of 0.5, 5, 40, and 150 mg/L were 96%, 73%, 42%, and 23%, respectively. CRP is a powerful prognostic marker for survival, and its prognostic value was superior to the IMDC risk model. This study highlights that CRP could be implemented as stratification factor for mRCC immunotherapy trials and potentially as an easy-to-use prognostic tool in the clinic.
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.CLGC.2021.11.010
Abstract: The discrimination performance of Bellmunt risk score for immune checkpoint inhibitor (ICI) therapy is largely unknown. This study aimed to validate and enhance discrimination of the Bellmunt score in patients with urothelial carcinoma treated with ICIs. Cox proportional hazard analysis were used to validate overall survival (OS) discrimination performance of the Bellmunt score in patients with urothelial carcinoma treated with atezolizumab in IMvigor210. The c-statistic (c) was used to evaluate the ability of C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), PD-L1 gene expression level on immune cells (PD-L1 ICs), albumin, time from prior chemotherapy, and tumor site count to enhance the Bellmunt score. External validation of an enhanced Bellmunt score utilized the independent atezolizumab arm of IMvigor211. In IMvigor210, Bellmunt score displayed moderate OS discrimination (c = 0.66). Addition of CRP (one point for CRP>30 mg/L) to the Bellmunt score resulted in greatest improvement in performance (c = 0.70), followed by NLR (c = 0.69). On external validation, CRP-Bellmunt score had superior performance (OS c = 0.67, PFS c = 0.60) than original Bellmunt score (OS c = 0.64, PFS c = 0.59) with 30% of patients reclassified into a higher risk group. Patients with CRP-Bellmunt score of 0, 1, 2, or 3-plus had 1-year OS probabilities of 63%, 44%, 21%, and 15%, respectively. CRP inclusion within the Bellmunt score enhanced the ability to discriminate high risk patients misclassified using the original model. We propose that the CRP-Bellmunt score may enable improved patient stratification in ICI clinical trials and provide more accurate prognostic information for patients with urothelial carcinoma initiating ICIs.
Publisher: Oxford University Press (OUP)
Date: 22-06-2023
DOI: 10.1093/RHEUMATOLOGY/KEAC357
Abstract: Sex is well known to influence risk, severity and treatment outcomes of RA, although the underlying causes are uncertain. The aim of this research was to examine whether factors influencing female sex hormones (reproductive status and exogenous sex hormone use) are associated with the efficacy of DMARDs. In idual participant data were pooled from five phase 3 clinical trials where RA patients were treated with tocilizumab and/or conventional synthetic DMARDs. The primary outcome was the time to first remission according to the Simplified Disease Activity Index. The relationship between menopausal status or use of exogenous sex hormones and the time of first remission was assessed via Cox proportional analysis. Analysed data included sex, baseline menopausal status (premenopausal, perimenopausal, early postmenopausal and postmenopausal), participant age, body mass index, race, number of previous DMARDs and baseline disease activity. Analysis included 4474 female patients, of whom 2817 (62.9%) were postmenopausal, 202 (4.5%) were early postmenopausal, 1021 (22.8%) were premenopausal and 414 (9.2%) were perimenopausal. Of these, 221 (7.8%), 13 (6.4%), 255 (25%) and 47 (11.4%), respectively, were taking exogenous sex hormones. In the pooled analysis, perimenopausal status was associated with reduced remission compared with premenopausal status [adjusted HR 0.78 (95% CI 0.61, 0.99)]. Sex hormone use was associated with significantly higher remission [adjusted HR 1.20 (95% CI 1.01, 1.43)]. Perimenopausal women were less likely to achieve remission compared with premenopausal RA patients. The use of exogenous sex hormones appeared to be associated with more frequent remission in female RA patients, particularly those who were perimenopausal and early postmenopausal, although further research is required to confirm and identify the drivers for this observation and how it interacts with menopausal status.
Publisher: American Society for Microbiology
Date: 03-2017
DOI: 10.1128/AAC.02401-16
Abstract: The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion ( P 0.01) and then backward deletion ( P 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability ( F ), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2023
DOI: 10.1200/JCO.2023.41.16_SUPPL.530
Abstract: 530 Background: Patient-reported outcomes (PROs) are captured in validated tools to provide the patients’ perspective and voice on their physical, social, emotional, functional, and cognitive abilities. Pre-treatment PROs have shown prognostic importance in other cancer types, however, the prognostic value of PROs in breast cancer has been minimally explored. Methods: In a pooled analysis of contemporary clinical trial IPD from patients with breast cancer, cox-proportional hazard analysis and binary logistic regression was used to assess the association between potential predictors with overall survival (OS) and adverse event (grade ≥ 3) outcomes, respectively. PROs were recorded using the EORTC QLQ-C30 version 3.0 questionnaire in the pooled cohort. Statistical significance was set at a threshold of P .05 and was determined via the likelihood ratio test. Model fit and linearity of variable associations were assessed via the Akaike information criterion (AIC). All analyses were stratified by age, performance status, treatment arm, and study. The primary assessed outcome was OS, with grade ≥ 3 adverse events assessed as a secondary outcome. A forward inclusion process (starting with the variable of lowest AIC, PRO domains were retained in the model if they decreased the AIC by 2 or more on addition, and remained statistically significant) was used to evaluate the value of multiple PRO domains on prognostic performances. Results: Within data available, the EORTC QLQ-C30 version 3.0 questionnaire was used in a pooled cohort of 8,544 patients across 8 clinicals trials. In the pooled cohort, the association between PROs and outcomes was best described by a linear association. Patient-reported physical functioning, appetite loss, and pain were significantly associated with OS. On forward-inclusion, only physical functioning remained within the OS prognostic model. Except for patient-reported financial difficulties, all PRO domains were significantly associated with grade ≥ 3 adverse events. On forward-inclusion, physical functioning, pain, and constipation all remained statistically significant. Conclusions: Within large high-quality IPD, pre-treatment PROs demonstrated significant prognostic relationships with therapeutic outcomes in patients with breast cancer initiating contemporary anticancer treatments. Patient-reported physical functioning was found to be the most prognostic PRO domain for OS, while patient-reported physical functioning, pain, and constipation were retained in a multivariable model prognostic of grade ≥ 3 adverse events.
Publisher: American Society for Microbiology
Date: 09-2015
DOI: 10.1128/AAC.00973-15
Abstract: Itraconazole is an orally active antifungal agent that has complex and highly variable absorption kinetics that is highly affected by food. This study aimed to develop a population pharmacokinetic model for itraconazole and the active metabolite hydroxyitraconazole, in particular, quantifying the effects of food and formulation on oral absorption. Plasma pharmacokinetic data were collected from seven phase I crossover trials comparing the SUBA-itraconazole and Sporanox formulations of itraconazole. First, a model of single-dose itraconazole data was developed, which was then extended to the multidose data. Covariate effects on itraconazole were then examined before extending the model to describe hydroxyitraconazole. The final itraconazole model was a 2-compartment model with oral absorption described by 4-transit compartments. Multidose kinetics was described by total effective daily dose- and time-dependent changes in clearance and bioavailability. Hydroxyitraconazole was best described by a 1-compartment model with mixed first-order and Michaelis-Menten elimination for the single-dose data and a time-dependent clearance for the multidose data. The relative bioavailability of SUBA-itraconazole compared to that of Sporanox was 173% and was 21% less variable between subjects. Food resulted in a 27% reduction in bioavailability and 58% reduction in the transit absorption rate constant compared to that with the fasted state, irrespective of the formulation. This analysis presents the most extensive population pharmacokinetic model of itraconazole and hydroxyitraconazole in the literature performed in healthy subjects. The presented model can be used for simulating food effects on itraconazole exposure and for performing prestudy power analysis and s le size estimation, which are important aspects of clinical trial design of bioequivalence studies.
Publisher: Elsevier BV
Date: 06-2022
Publisher: MDPI AG
Date: 11-11-2022
Abstract: Cancer of the central nervous system (CNS) is ranked as the 19th most prevalent form of the disease in 2020. This study aims to identify candidate biomarkers and metabolic pathways affected by paclitaxel and etoposide, which serve as potential treatments for glioblastoma, and are linked to the pathogenesis of glioblastoma. We utilized an untargeted metabolomics approach using the highly sensitive ultra-high-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) for identification. In this study, 92 and 94 metabolites in U87 and U373 cell lines were profiled, respectively. The produced metabolites were then analyzed utilizing t-tests, volcano plots, and enrichment analysis modules. Our analysis revealed distinct metabolites to be significantly dysregulated (nutriacholic acid, L-phenylalanine, L-arginine, guanosine, ADP, hypoxanthine, and guanine), and to a lesser extent, mevalonic acid in paclitaxel and/or etoposide treated cells. Furthermore, both urea and citric acid cycles, and metabolism of polyamines and amino acids (aspartate, arginine, and proline) were significantly enriched. These findings can be used to create a map that can be utilized to assess the antitumor effect of paclitaxel and/or etoposide within the studied cancer cells.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2021
DOI: 10.1038/S41523-021-00241-9
Abstract: While many studies have evaluated the relationship between BMI and breast cancer outcomes, it is unclear whether this relationship is consistent between early breast cancer (BC) and advanced BC. The study included 5099 patients with HER2 positive early BC (EBC) and 3496 with HER2 positive advanced BC (ABC). In the EBC cohort, higher BMI was associated with worse overall survival (OS) (HR [95% CI]: overweight = 1.30 [1.13–1.51] obese = 1.37 [1.14–1.64], P = 0.001), and worse disease-free survival (overweight = 1.10 [0.98–1.24] obese = 1.20 [1.04–1.39], P = 0.061). In contrast, for the ABC cohort, higher BMI was significantly associated with improved OS (overweight = 0.85 [0.76–0.96] obese = 0.82 [0.72–0.95], P = 0.014), and progression-free survival (overweight = 0.91 [0.83–1.01] obese = 0.87 [0.77–0.98], P = 0.034). In this large high-quality dataset, higher BMI was independently associated with worse survival in EBC, paradoxically in ABC higher BMI was independently associated with improved survival.
Publisher: American Medical Association (AMA)
Date: 09-2022
DOI: 10.1001/JAMAONCOL.2022.2867
Abstract: Emerging policies drafted by the pharmaceutical industry indicate that they will transparently share clinical trial data. These data offer an unparalleled opportunity to advance evidence-based medicine and support decision-making. To evaluate the eligibility of independent, qualified researchers to access in idual participant data (IPD) from oncology trials that supported US Food and Drug Administration (FDA) approval of new anticancer medicines within the past 10 years. In this quality improvement study, a cross-sectional analysis was performed of pivotal clinical trials whose results supported FDA-approved anticancer medicines between January 1, 2011, and June 30, 2021. These trials’ results were identified from product labels. Eligibility for IPD sharing was confirmed by identification of a public listing of the trial as eligible for sharing or by receipt of a positive response from the sponsor to a standardized inquiry. The main outcome was frequency of IPD sharing eligibility. Reasons for data sharing ineligibility were requested and collated, and company-, drug-, and trial-level subgroups were evaluated and presented using χ 2 tests and forest plots. During the 10-year period examined, 115 anticancer medicines were approved by the FDA on the basis of evidence from 304 pharmaceutical industry–sponsored trials. Of these trials, 136 (45%) were eligible for IPD sharing and 168 (55%) were not. Data sharing rates differed substantially among industry sponsors, with the most common reason for not sharing trial IPD being that the collection of long-term follow-up data was still ongoing (89 of 168 trials [53%]). Of the top 10 anticancer medicines by global sales, nivolumab, pembrolizumab, and pomalidomide had the lowest eligibility rates for data sharing (& % of trials). There has been a substantial increase in IPD sharing for industry-sponsored oncology trials over the past 5 years. However, this quality improvement study found that more than 50% of queried trials for FDA-approved anticancer medicines were ineligible for IPD sharing. Data accessibility would be substantially improved if, at the time of FDA registration of a medicine, all data that support the registration were made available.
Publisher: Elsevier BV
Date: 2022
Publisher: Springer Science and Business Media LLC
Date: 28-10-2021
No related grants have been discovered for Ahmad Abuhelwa.