Population Pharmacokinetics of Candesartan in Patients with Chronic Heart Failure

Abstract

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 total of 281 white patients were included to develop the Pop‐PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7–22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF.

Population Pharmacokinetics of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: An Integrated Analysis

“…It has been suggested that the PK of drugs in patients with heart failure could differ from those of healthy participants, due to the pathophysiological changes that occur in heart failure and their potential to affect the PK of drugs 15–17 . Indeed, edema and thickening of the gut wall are thought to contribute to the decrease in the absorption of drugs, such as furosemide and candesartan, in patients with heart failure 11,18,19,20 . However, these drugs are Biopharmaceutics Classification System class 4 drugs with low permeability, which makes them susceptible to factors affecting intestinal absorption in heart failure.…”

“…Patients with heart failure undergo pathological changes in multiple organs that can have the potential to affect the PK of drugs. 11 The PPK analysis presented here combines data from SOCRATES-REDUCED and VICTORIA. SOCRATES-REDUCED provides data from multiple dose levels with PK sampled around T max and trough, facilitating structural model development, whereas VICTORIA provides sparse samples from a large, diverse, global population, facilitating covariate analyses.…”

“…This model identified bilirubin and creatinine clearance as covariates influencing vericiguat PK, but the sample size was not large enough to fully assess the impact of disease‐related factors such as left ventricular ejection fraction, New York Heart Association (NYHA) class, and NT‐proBNP. Patients with heart failure undergo pathological changes in multiple organs that can have the potential to affect the PK of drugs 11 . The PPK analysis presented here combines data from SOCRATES‐REDUCED and VICTORIA.…”

Reducing the risk of chronic heart failure development in patients with arterial hypertension from the position of evidence medicine (focus on candesartan)

“…При применении кандесартана у больных с ХСН рекомендуется учитывать индивидуальные особенности пациента: массу тела, СКФ, наличие СД и более индивидуальный подход к дозировке препарата, начиная с 4 мг с постепенным увеличением дозы до клинически эффективной с медленными этапами титрования (максимально до 32 мг/сут) [44].…”

Pharmacological Profile of Loop Diuretic in Experimental Model of Heart Failure

“…Such models allow not only, together with clinical research, the discovery of new drugs (10), but also contribute to a better understanding of a gap regarding this topic: the effect that HF has on pharmacodynamic and kinetic characteristics (11). In the literature, several advances have been made in this aspect within population studies (12,13), but within experimental research, studies and models that can significantly detect such changes are still scarce.…”