A Phase 1 First-in-Human Single-Ascending-Dose Trial With ESB1609, a Selective Agonist to the Sphingosine-1-Phosphate Receptor 5.

ESB1609 is a small-molecule sphingosine-1-phosphate-5 receptor-selective agonist designed to restore lipid homeostasis by promoting cytosolic egress of sphingosine-1-phosphate to reduce abnormal levels of ceramide and cholesterol in disease. A phase 1 study was conducted in healthy volunteers to determine the safety, tolerability, and pharmacokinetics of ESB1609. Following single oral doses, ESB1609 demonstrated linear pharmacokinetics in plasma and cerebrospinal fluid (CSF) for formulations containing sodium laurel sulfate. Plasma and CSF median time to maximum drug concentration (tmax ) were reached by 4-5 hours and 6-10 hours, respectively. The delay in achieving tmax in CSF relative to plasma, likely due to the high protein binding of ESB1609, was also observed in 2 rat studies. Continuous CSF collection via indwelling catheters confirmed that a highly protein-bound compound is measurable and established the kinetics of ESB1609 in human CSF. Mean plasma terminal elimination half-lives ranged from 20.2 to 26.8 hours. The effect of either a high-fat or standard meal increased maximum plasma concentration and area under the concentration-time curve from time 0 to infinity compared to the fasted state by 2.42-4.34-fold higher, but tmax and half-life remained the same irrespective of fed state. ESB1609 crosses the blood-brain barrier with CSF:plasma ratios ranging between 0.04% and 0.07% across dose levels. ESB1609 demonstrated a favorable safety and tolerability profile at exposures expected to be efficacious.

The role of concentration-effect relationships in the assessment of QTc interval prolongation.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) modelling has been widely used in clinical research. Yet, its application in the evaluation of cardiovascular safety remains limited, particularly in the evaluation of pro-arrhythmic effects. Here we discuss the advantages of disadvantages of population PKPD modelling and simulation, a paradigm built around the knowledge of the concentration-effect relationship as the basis for decision making in drug development and its utility as a guide to drug safety. A wide-ranging review of the literature was performed on the experimental protocols currently used to characterize the potential for QT interval prolongation, both pre-clinically and clinically. Focus was given to the role of modelling and simulation for design optimization and subsequent analysis and interpretation of the data, discriminating drug from system specific properties. Cardiovascular safety remains one of the major sources of attrition in drug development with stringent regulatory requirements. However, despite the myriad of tests, data are not integrated systematically to ensure accurate translation of the observed drug effects in clinically relevant conditions. The thorough QT study addresses a critical regulatory question but does not necessarily reflect knowledge of the underlying pharmacology and has limitations in its ability to address fundamental clinical questions. It is also prone to issues of multiplicity. Population approaches offer a paradigm for the evaluation of drug safety built around the knowledge of the concentration-effect relationship. It enables quantitative assessment of the probability of QTc interval prolongation in patients, providing better guidance to regulatory labelling and understanding of benefit/risk in specific populations.