Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure.
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ABSTRACT:
SUBMITTER: Kassem I
PROVIDER: S-EPMC7877833 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure.
Kassem Imad I Sanche Steven S Li Jun J Bonnefois Guillaume G Dubé Marie-Pierre MP Rouleau Jean-Lucien JL Tardif Jean-Claude JC White Michel M Turgeon Jacques J Nekka Fahima F de Denus Simon S
Clinical and translational science 20200828 1
Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop-PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed-Effects Modeling (NONMEM) and R software. A to ...[more]
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Project description:ObjectiveThe purpose of this study was to identify predictors of incident diabetes during follow-up of nondiabetic patients with chronic heart failure (CHF) in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) program.Research design and methodsA total of 1,620 nondiabetic patients had full baseline datasets. We compared baseline demographic, medication, and laboratory data for patients who did or did not develop diabetes and conducted logistic regression and receiver operator characteristic curve analyses.ResultsOver a median period of 2.8 years, 126 of the 1,620 patients (7.8%) developed diabetes. In multiple logistic regression analysis, the following baseline characteristics were independently associated with incident diabetes in decreasing order of significance by stepwise selection: higher A1C (odds ratio [OR] 1.78 per 1 SD increase; P < 0.0001), higher BMI (OR 1.64 per 1 SD increase; P < 0.0001), lipid-lowering therapy (OR 2.05; P = 0.0005), lower serum creatinine concentration (OR 0.68 per 1 SD increase; P = 0.0018), diuretic therapy (OR 4.81; P = 0.003), digoxin therapy (OR 1.65; P = 0.022), higher serum alanine aminotransferase concentration (OR 1.15 per 1 SD increase; P = 0.027), and lower age (OR 0.81 per 1 SD increase; P = 0.048). Using receiver operating characteristic curve analysis, A1C and BMI yielded areas under the curve of 0.723 and 0.712, respectively, increasing to 0.788 when combined. Addition of other variables independently associated with diabetes risk minimally improved prediction of diabetes.ConclusionsIn nondiabetic patients with CHF in CHARM, A1C and BMI were the strongest predictors of the development of diabetes. Other minor predictors in part reflected CHF severity or drug-associated diabetes risk. Identifying patients with CHF at risk of diabetes through simple criteria appears possible and could enable targeted preventative measures.
| S-EPMC2671104 | biostudies-literature
Project description:Measuring genome-wide changes in transcript abundance in circulating peripheral whole blood cells is a useful way to study disease pathobiology and may help elucidate biomarkers and molecular mechanisms of disease. The sensitivity and interpretability of analyses carried out in this complex tissue, however, are significantly affected by its heterogeneity. It is therefore desirable to quantify this heterogeneity, either to account for it or to better model interactions that may be present between the abundance of certain transcripts, some cell types and some indication. Accurate enumeration of the many component cell types that make up peripheral whole blood can be costly, however, and may further complicate the sample collection process. Many approaches have been developed to infer the composition of a sample from high-dimensional transcriptomic and, more recently, epigenetic data. These approaches rely on the availability of isolated expression profiles for the cell types to be enumerated. These profiles are platform-specific, suitable datasets are rare, and generating them is expensive. No such dataset exists on the Affymetrix Gene ST platform. We present a freely-available, and open-source, multiresponse Gaussian model capable of accurately inferring the composition of peripheral whole blood samples from Affymetrix Gene ST expression profiles. The model was developed on a cohort of patients with chronic obtructive pulmonary disease and tested in chronic heart failure patients.
2016-05-25 | GSE77343 | GEO
Project description:BackgroundVericiguat, a stimulator of soluble guanylate cyclase, has been developed as a first-in-class therapy for worsening chronic heart failure in adults with left ventricular ejection fraction < 45%.ObjectiveThe objective of this article was to characterize the pharmacokinetics and pharmacokinetic variability of vericiguat combined with guideline-directed medical therapy (standard of care), and identify exposure-response relationships for safety (hemodynamics) and pharmacodynamic markers of efficacy (N-terminal pro-B-type natriuretic peptide concentration [NT-proBNP]) in patients with heart failure and left ventricular ejection fraction < 45% in the SOCRATES-REDUCED study (NCT01951625).MethodsVericiguat and NT-proBNP plasma concentrations in 454 and 432 patients in SOCRATES-REDUCED, respectively, were analyzed using nonlinear mixed-effects modeling.ResultsVericiguat pharmacokinetics were well described by a one-compartment model with apparent clearance, apparent volume of distribution, and absorption rate constant. Age, bodyweight, plasma bilirubin, and creatinine clearance were identified as significant covariates on apparent clearance; sex and bodyweight on apparent volume of distribution; and bodyweight and plasma albumin level on absorption rate constant. Pharmacokinetic/pharmacodynamic analysis showed initial minor and transient effects of vericiguat on blood pressure with low clinical impact. There were no changes in heart rate following initial or repeated vericiguat administration. An exposure-dependent and time-dependent turnover pharmacokinetic/pharmacodynamic model for NT-proBNP described production and elimination rates and an demonstrated exposure-dependent reduction in [NT-proBNP] by vericiguat plus standard of care compared with placebo plus standard of care. This effect was dependent on baseline [NT-proBNP].ConclusionsVericiguat has predictable pharmacokinetics, with no long-term effects on blood pressure in patients with heart failure and left ventricular ejection fraction < 45%. A pharmacokinetic/pharmacodynamic model described a vericiguat exposure-dependent reduction of NT-proBNP.Clinical trial identifierNCT01951625.
| S-EPMC8585847 | biostudies-literature
Project description:BackgroundToday, heart failure is one of the leading causes of death and disability in most developed and developing countries. By 2030, more than 23.3 million people are projected to die of cardiovascular diseases each year, and the prevalence of heart failure is expected to increase by 25%. One of the preventive interventions is pharmacological interventions which can be used to reduce the complications of cardiovascular diseases such as heart failure. One of the most important pharmacological interventions in patients with heart failure is the use of antihypertensive drugs such as candesartan, enalapril, and valsartan. This study aimed to compare the cost-utility of candesartan, enalapril, and valsartan in patients with heart failure using the Markov model in Iran in 2020.MethodsIn the present study, a four-state Markov model was designed to compare the cost-utility of candesartan, enalapril, and valsartan for a hypothetical cohort of 10,000 heart failure patients older than 24 years. The payers' perspective was used to calculate the costs. The Markov states included outpatients with heart failure, patients with heart failure admitted to general hospital wards, patients with heart failure admitted to the intensive care units (ICUs), and death. The effectiveness measure in this study was the quality-adjusted life years (QALYs). The one-way and probabilistic sensitivity analyses were used to determine the robustness of the results. The TreeAge Pro 2011 software was used for data analysis.ResultsThe results showed that the average expected costs and QALYs were 119645.45 USD and 16.15 for valsartan, 113,019.68 USD and 15.16 for enalapril, and 113,093.37 USD and 15.06 for candesartan, respectively. Candesartan was recognized as the dominated option. Because the calculated incremental cost-effectiveness ratio (ICER) value (6,692.69 USD) was less than the threshold value (7,256 USD), valsartan was cost-effective compared to enalapril. The results of the cost-effectiveness acceptability curve showed that at the threshold of 7,256 USD, valsartan had a 60% chance of being cost-effective compared to enalapril. The results of one-way and probabilistic sensitivity analyses confirmed the robustness of the results. Moreover, the results showed that ICU (1,112 USD) had the highest cost among cost items.ConclusionAccording to the results, it is recommended that health policymakers consider the use of valsartan by cardiologists when designing clinical guidelines for the treatment of patients with heart failure.
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Project description:AIMS:Serelaxin is a recombinant human relaxin-2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. METHODS:Serum concentration-time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed-effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. RESULTS:A three-compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady-state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady-state volume of distribution (Vss) was higher in patients with AHF (544 ml kg-1 ) or chronic heart failure (434 ml kg-1 ), compared with typical nonheart failure subjects (347 ml kg-1 ). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively. CONCLUSIONS:Patients with HF showed higher Vss but similar clearance (and therefore steady-state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady-state concentration was moderate and therefore unlikely to be clinically relevant.
| S-EPMC6177704 | biostudies-literature
Project description:AimsThe Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin-converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan.MethodsWe performed genome-wide association studies in 2727 patients of European ancestry from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan-treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint.ResultsWe found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55-2.35; P = 1.7 × 10-9 ). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome-wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene-level collapsing analysis.ConclusionsWe have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings.
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Project description:AimsAlthough diabetes mellitus (DM) is a common co-morbidity in chronic heart failure (HF) patients, European data on concurrent HF and DM treatment are lacking. Therefore, we have studied the HF treatment of patients with and without DM. Additionally, with the recent breakthrough of sodium-glucose cotransporter 2 (SGLT2) inhibitors in the field of HF, we studied the potential impact of this new drug in a large cohort of HF patients.Methods and resultsA total of 7488 patients with chronic HF with a left ventricular ejection fraction <50% from 34 Dutch outpatient HF clinics between 2013 and 2016 were analysed on diabetic status and background HF therapy. Average age of the total population was 72.8 years (±11.7 years), and 64% of the patients were male. Diabetes was present in 29% of the patients (N = 2174). Diabetics had a worse renal function (mean estimated glomerular filtration rate 56 vs. 61 mL/min/1.73 m2 , P < 0.001). Renin-angiotensin system inhibitors were less often prescribed in diabetics compared with non-diabetics (79% vs. 82%, P = 0.001), while no significant differences regarding other guideline-recommended HF drugs were found. Target doses of beta-blockers (23% vs. 16%, P < 0.001), renin-angiotensin system inhibitors (47% vs. 43%, P = 0.009), and mineralocorticoid receptor antagonists (57% vs. 51%, P = 0.005) were more often prescribed in diabetics than non-diabetics. Based on the latest trials on SGLT2 inhibitors, 31-64% of all HF patients would fulfil the eligibility or enrichment criteria (with vs. without N-terminal prohormone BNP criterion).ConclusionsIn this large real-world HF registry, a high prevalence of DM was observed and diabetics more often received guideline-recommended target doses. Based on current evidence, the majority of patients would fulfil the enrichment criteria of SGLT2 trials in HF and the impact of this new drug class will be large.
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Project description:BACKGROUND:Chronic heart failure (CHF) is the most common reason for hospital admissions in Germany. For the National Disease Management Guideline (NDMG) on CHF, a multidisciplinary expert panel revised the chapters on drug therapy, invasive therapy, and care coordination, following the methods of evidence-based medicine. METHODS:Recommendations are based on international guideline adaptations or systematic literature search. They were developed by a multidisciplinary expert panel, approved in a formal consensus procedure, and tested in open consultation, as specified by the requirements for S3 guidelines. RESULTS:The pharmacological treatment is based on ACE inhibitors, beta-blockers and mineralocorticoid receptor antagonists as well as diuretics to treat fluid retention, if present. Sacubitril/Valsartan and ivabradine showed positive effects on mortality in large but methodologically limited RCT. They are recommended if established combination therapy is not sufficient for symptom control, or if drugs are not tolerated/contraindicated. The indications for pacemakers or defibrillators have been confined to patient subgroups in which clinical trials have shown a clear benefit. Moreover, the goals of treatment and the patient's expectations should be aligned with each other. Structured care programs, specialized nurses, remote, or telephone monitoring showed moderate effects on patient related outcomes in RCT. CONCLUSION:All patients with heart failure are suggested to be enrolled in a structured program (e.g., a disease management program) including coordinated multidisciplinary care and continuous educational interventions. In patients with a poor prognosis, more intensive care is recommended, e.g. specialized nurses, or telephone support.
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Project description:In developed countries, it is estimated that more than 10 % of adults aged over 70 years have heart failure (HF). Despite therapeutic advances, it remains a condition associated with significant morbidity and mortality. It is one of the commonest causes of unscheduled hospital admissions in older adults and data consistently show a lower uptake of evidence-based investigations and therapies as well as higher rates of HF hospitalisations and mortality than in younger adults. These rates are highest amongst patients discharged to 'skilled nursing facilities', where comorbidities, frailty and cognitive impairment are common and have a significant impact on outcomes. In this review, we examine current guidance and its limitations and offer a pragmatic approach to management of HF in this elderly population.
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Project description:Congestion, or fluid overload, is a classic clinical feature of patients presenting with heart failure patients, and its presence is associated with adverse outcome. However, congestion is not always clinically evident, and more objective measures of congestion than simple clinical examination may be helpful. Although diuretics are the mainstay of treatment for congestion, no randomised trials have shown the effects of diuretics on mortality in chronic heart failure patients. Furthermore, appropriate titration of diuretics in this population is unclear. Research is required to determine whether a robust method of detecting - and then treating - subclinical congestion improves outcomes.
| S-EPMC5490880 | biostudies-literature