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.

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.

Cultural diversity teaching and issues of uncertainty: the findings of a qualitative study.

BACKGROUND: There is considerable ambiguity in the subjective dimensions that comprise much of the relational dynamic of the clinical encounter. Comfort with this ambiguity, and recognition of the potential uncertainty of particular domains of medicine (e.g.--cultural factors of illness expression, value bias in diagnoses, etc) is an important facet of medical education. This paper begins by defining ambiguity and uncertainty as relevant to clinical practice. Studies have shown differing patterns of students' tolerance for ambiguity and uncertainty that appear to reflect extant attitudinal predispositions toward technology, objectivity, culture, value- and theory-ladeness, and the need for self-examination. This paper reports on those findings specifically related to the theme of uncertainty as relevant to teaching about cultural diversity. Its focus is to identify how and where the theme of certainty arose in the teaching and learning of cultural diversity, what were the attitudes toward this theme and topic, and how these attitudes and responses reflect and inform this area of medical pedagogy. METHODS: A semi-structured interview was undertaken with 61 stakeholders (including policymakers, diversity teachers, students and users). The data were analysed and themes identified. RESULTS: There were diverse views about what the term cultural diversity means and what should constitute the cultural diversity curriculum. There was a need to provide certainty in teaching cultural diversity with diversity teachers feeling under considerable pressure to provide information. Students discomfort with uncertainty was felt to drive cultural diversity teaching towards factual emphasis rather than reflection or taking a patient centred approach. CONCLUSION: Students and faculty may feel that cultural diversity teaching is more about how to avoid professional, medico-legal pitfalls, rather than improving the patient experience or the patient-physician relationship. There may be pressure to imbue cultural diversity issues with levels of objectivity and certainty representative of other aspects of the medical curriculum (e.g.--biochemistry). This may reflect a particular selection bias for students with a technocentric orientation. Inadvertently, medical education may enhance this bias through training effects, and accommodate disregard for subjectivity, over-reliance upon technology and thereby foster incorrect assumptions of objective certainty. We opine that it is important to teach students that technology cannot guarantee certainty, and that dealing with subjectivity, diversity, ambiguity and uncertainty is inseparable from the personal dimension of medicine as moral enterprise. Uncertainty is inherent in cultural diversity so this part of the curriculum provides an opportunity to address the issue as it relates to patient care.

An open-label study to determine the pharmacokinetics and safety of migalastat HCl in subjects with impaired renal function and healthy subjects with normal renal function.

OBJECTIVES: Renal function may progressively decline in patients with Fabry disease. This study assessed pharmacokinetics, safety, and tolerability of a single oral dose of migalastat HCl 150 mg in subjects with normal or mildly, moderately, or severely impaired renal function. METHODS: Volunteers were enrolled into two cohorts stratified for renal function calculated using the Cockcroft-Gault equation for creatinine clearance. Pharmacokinetic parameters determined were: area under the concentration-time curve (AUC) from time zero to the last measurable concentration postdose (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), maximum observed concentration (Cmax ), time to Cmax (tmax ), concentration at 48 hours postdose (C48h ), terminal elimination half-life (t1/2 ), oral clearance (CL/F), and apparent terminal elimination rate constant (λz) (ClinicalTrials.gov registration: NCT01730469). RESULTS: Thirty-two subjects enrolled and completed the study (Cohort 1: n = 24; Cohort 2: n = 8). Migalastat clearance decreased with increasing renal impairment, resulting in increases in migalastat HCl plasma t1/2 , AUC0-∞ , and C48h compared with subjects with normal renal function. Incidence of adverse events was comparable across all renal function groups. CONCLUSIONS: Plasma migalastat clearance decreased as degree of renal impairment increased. Data from the migalastat HCl clinical program will guide dosing and intervals for patients with Fabry disease with renal impairment.