This article highlights the potential for personalized aquaretic therapy and identifies critical safety and monitoring protocols necessary for optimizing clinical outcomes by integrating structural, metabolic, and genetic data.
Abstract
Vaptans are non-peptide arginine vasopressin (AVP) receptor antagonists essential for modulating water homeostasis. This review evaluates their chemical evolution from peptide analogs to orally bioavailable molecules and summarizes the pharmacokinetic profiles of key agents, including tolvaptan, conivaptan, and mozavaptan. Significant emphasis is placed on the clinical role of tolvaptan as a disease-modifying therapy in autosomal dominant polycystic kidney disease (ADPKD) and its efficacy in syndrome of inappropriate antidiuretic hormone secretion (SIADH). Furthermore, the impact of pharmacogenetic factors, especially CYP3A5 and SVEP1 polymorphisms, is explored as a potential source of inter-individual variability in treatment response. By integrating structural, metabolic, and genetic data, this article highlights the potential for personalized aquaretic therapy and identifies critical safety and monitoring protocols necessary for optimizing clinical outcomes.
This review provides a general overview of the physiological effects and pharmacokinetic properties that affect the absorption, distribution, metabolism, and elimination of recently developed antihypertensive drugs, such as fimasartan, azilsartan, zilebesiran, aprocitentan, and esaxerenone. It provides an opportunity to understand the pharmacologic properties of drugs like esaxerenone, a non-steroidal selective mineralocorticoid receptor antagonist; aprocitentan, a dual endothelin receptor antagonist; and zilebesiran, a small interfering RNA (siRNA) therapeutic that inhibits hepatic angiotensinogen synthesis. Mechanistic differences among these agents are also highlighted; for instance, fimasartan and azilsartan inhibit the angiotensin II receptor, whereas other medications alter mineralocorticoid activity or endothelial pathways. The review further discusses the clinical implications of these mechanisms in hypertension management and supports informed therapeutic decisionmaking by providing a detailed understanding of the pharmacological and mechanistic profiles of these emerging antihypertensive therapies.
Pritesh Mahajan, Ashish Pagar, Kajal Baviskar et al.· Current hypertension reviews· 0 citations
Anakinra, an interleukin-1 receptor antagonist (IL-1Ra), has been used clinically for over 20 years, with growing interest in repurposing it across diverse indications. However, clinical dosing strategies for anakinra are variable, with limited pharmacokinetic (PK)/pharmacodynamic (PD) knowledge across patient populations and administration routes available. This systematic review aimed to summarise clinical PK and PD characteristics of anakinra and identify research gaps. A systematic search of Medline, Embase, and other databases was conducted to identify clinical studies reporting the PK, PD, efficacy, and safety of anakinra. Following the application of predefined inclusion and exclusion criteria, 26 articles were included in the review. Extracted data from these studies were converted into uniform units to enable cross-study comparison, and a descriptive synthesis was performed. All included studies were assessed for risk of bias. Data were categorised into three groups: noncompartmental analysis (NCA) PK parameters, model-informed PK/PD parameters, and exposure–response (ER) relationships. Across all studies, anakinra demonstrated linear PK following both intravenous (IV) and subcutaneous (SC) administration, with high SC bioavailability and flip-flop kinetics. Covariate analyses from NCA and PK models consistently identified body weight and renal function as key determinants of anakinra PK variability, with clearance increasing with body weight and decreasing with worsening renal function. ER analyses identify a potential target exposure corresponding to an average steady-state concentration (Cavg,ss) of 0.4 mg/L, equivalent to a steady-state area under the concentration–time curve (AUC0–24 h,ss) of 9.6 mg·h/L. However, available anakinra paediatric clinical PK data are sparse, limiting definitive age-based comparisons. Existing PK models of anakinra lacked incorporation of endogenous IL-1Ra kinetics, and do not currently describe diverse patient populations, with only one population PK/PD model identified. Furthermore, currently available data are insufficient to validate the target exposure of anakinra across the full continuum spanning PK, PD, clinical outcomes, and safety. Overall, this review highlights substantial gaps in the clinical PK/PD knowledge on anakinra, and model robustness. Future studies, integrating physiologically informed covariates, improved biomarker strategies, and comprehensive ER data, are essential to support model-informed dosing for anakinra repurposing across populations and administration routes. These would facilitate the safety and efficacy of anakinra therapy across diverse populations.
Jia Li, Megan Clark, D. Metz et al.· Clinical Pharmacokinetics· 0 citations
Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin–angiotensin–aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension management. Through N-acetylgalactosamine-mediated hepatic delivery, zilebesiran selectively silences angiotensinogen (AGT) messenger RNA, the transcript encoding the common precursor of all angiotensin peptides. This upstream intervention reduces AGT production and produces durable blood pressure lowering that can persist for up to 6 months after a single dose. This review summarizes the mechanism of action of zilebesiran, its pharmacokinetic and pharmacodynamic properties, and the available phase 1 and phase 2 clinical evidence, including the KARDIA program. We also place zilebesiran within the evolving antihypertensive landscape by comparing it with aldosterone synthase inhibitors, dual endothelin receptor antagonists, and brain aminopeptidase A inhibitors. Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway.
M. Francese, Lucio Giuseppe Granata, A. Noor et al.· Life· 0 citations
Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data. Methods: The 3- and 14-day effects of 40 mg/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARα). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age. Results: Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively. Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment.
Yuchen Qu, Zhuan Yang, Wen Ma et al.· Pharmaceutics· 0 citations
INTRODUCTION
Glucagon-like peptide-1 receptor agonists (GLP-1RA) have emerged as key drug class in the management of the cardio-nephro-metabolic continuum. Their effects extend to cardiac, vascular, and renal systems, providing a pathophysiological basis for the results of cardiovascular outcomes trials. Their pharmacokinetic properties substantially contribute, as structural modifications prolonged plasma half-life and increased systemic exposure through resistance to enzymatic degradation, albumin binding, and optimization of molecular size.
AREAS COVERED
This review integrates current evidence on pharmacokinetics, pharmacodynamics, and clinical effects of GLP-1RA focusing on the heart, vascular system, and kidney. A literature search until March 2026 was performed using MEDLINE, EMBASE, Google Scholar, Web of Science, and the Cochrane Controlled Trials Register. GLP-1RA exert modest chronotropic effects and cardiac protection in ischemia-reperfusion, although direct myocardial effects remain incompletely defined. Vascular benefits seem mediated by improved endothelial function, reduced oxidative stress, and modulation of nitric oxide pathways. In the kidney, GLP-1RA modulate proximal tubular sodium reabsorption and tubule-glomerular feedback, leading to reduced albuminuria and slower renal function decline. Clinical trials and meta-analyses documented reductions in major cardiovascular and renal outcomes.
EXPERT OPINION
In our view, pharmacokinetics is a major determinant of the clinical profile of GLP-1RA, beyond glycemic control alone.
Ivano Barnaba, Francesco Massari, M. Ciccone et al.· Expert Opinion on Drug Metab...· 0 citations
Phenytoin, an antiepileptic drug known for its complex
pharmacokinetics and narrow therapeutic range, may interact with garlic (Allium sativum).
Garlic affects CYP450 enzymes and P-glycoprotein, potentially affecting the metabolism,
transport, efficacy, and toxicity of phenytoin. This systematic review aims to
assess the existing evidence regarding pharmacokinetic and pharmacodynamic interactions
between garlic and phenytoin.
A thorough literature review was performed utilizing PubMed, Scopus, Web of
Science, ScienceDirect, and Google Scholar. Relevant research was examined and integrated
in accordance with PRISMA criteria to present a summary of existing knowledge.
Data from in vitro studies, animal models, and restricted clinical reports were examined to
evaluate the influence of garlic on phenytoin absorption, metabolism, plasma levels, and
treatment effectiveness. Mechanistic findings, heterogeneity in garlic formulations, and
therapeutic implications for epilepsy management were also examined.
In vitro and pharmacokinetic studies indicate that garlic may either increase or
inhibit the metabolism of phenytoin. However, conclusive determinations cannot be
drawn owing to the lack of substantial human research.
Available findings suggest a potential interaction between garlic and phenytoin
involving CYP450 enzymes and P-glycoprotein. However, inconsistent experimental
outcomes and inadequate clinical evidence prevent definitive conclusions. The variability
of garlic formulations hampers interpretation, highlighting the necessity for careful clinical
application and rigorously planned human trials in epilepsy management.
Clinicians should exercise vigilance and systematically inquire about garlic
consumption in patients undergoing phenytoin therapy. Controlled clinical trials are necessary
to validate these findings and ascertain the safety of garlic in combination with
phenytoin.
D. Lm, Asha Nayak, Vaishnavi B et al.· Current Pharmacogenomics and...· 0 citations