An Industry Survey With Focus on Cardiovascular Safety Pharmacology Study Design and Data Interpretation.

INTRODUCTION: The Safety Pharmacology Society (SPS) conducted a membership survey to examine industry practices related mainly to cardiovascular (CV) safety pharmacology (SP). METHODS: Questions addressed nonclinical study design, data analysis methods, drug-induced effects, and conventional and novel CV assays. RESULTS: The most frequent therapeutic area targeted by drugs developed by the companies/institutions that employ survey responders was oncology. The most frequently observed drug-mediated effects included an increased heart rate, increased arterial blood pressure, hERG (IKr) block, decreased arterial blood pressure, decreased heart rate, QTc prolongation, and changes in body temperature. Broadly implemented study practices included Latin square crossover study design with n = 4 for nonrodent CV studies, statistical analysis of data (eg, analysis of variance), use of arrhythmia detection software, and the inclusion of data from all study animals when integrating SP studies into toxicology studies. Most responders frequently used individual animal housing conditions. Responders commonly evaluated drug effects on multiple ion channels, but in silico modeling methods were used much less frequently. Most responders rarely measured the J-Tpeak interval in CV studies. Uncertainties relative to Standard for Exchange of Nonclinical Data applications for data derived from CV SP studies were common. Although available, the use of human induced pluripotent stem cell cardiomyocytes remains rare. The respiratory SP study was rarely involved with identifying drug-induced functional issues. Responders indicated that the study-derived no observed effect level was more frequently determined than the no observed adverse effect level in CV SP studies; however, a large proportion of survey responders used neither.

The state of the art in secondary pharmacology and its impact on the safety of new medicines.

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development. Based on our analysis of this survey and discussions and additional research within the group, we present here an overview of the current state of the art in secondary pharmacology screening. We discuss best practices, including additional safety-associated targets not covered by most current screening panels, and present approaches for interpreting and reporting off-target activities. We also provide an assessment of the safety impact of secondary pharmacology screening, and a perspective on opportunities and challenges in this rapidly developing field.

Inhibition of smooth muscle myosin as a novel therapeutic target for hypertension.

We examined a novel therapeutic approach for hypertension, a small-molecule direct inhibitor of smooth muscle myosin, CK-2018448 (CK-448), which is an N,N'-alkylurea (U.S. Patent Publication 2009-0275537 A1) in conscious dogs with renal hypertension and compared its efficacy with that of a calcium channel blocker, amlodipine. Dogs were instrumented with a miniature left ventricular pressure gauge, an aortic pressure catheter, and ultrasonic flow probes in the ascending aorta and renal and iliac arteries for measurement of cardiac output and regional blood flow. In the hypertensive state, mean arterial pressure increased from 101 ± 3.8 to 142 ± 1.9 mm Hg. At the doses selected, CK-448 and amlodipine increased cardiac output similarly (30 ± 11% versus 33 ± 6.4%) and similarly reduced mean arterial pressure (-22 ± 3.6% versus -16 ± 3.4%) and total peripheral resistance (-36 ± 5.9% versus -37 ± 5.8%). CK-448 had the greatest vasodilator effect in the renal bed, where renal blood flow increased by 46 ± 9.0%, versus 11 ± 3.4% for amlodipine (p < 0.01). CK-488 produced significantly less vasodilation in the limb, where iliac blood flow did not change; in contrast, it rose by 48 ± 12% with amlodipine (p < 0.01). The minimal effects on limb blood flow could limit the development of peripheral edema, an adverse side effect of Ca(2+) channel blockers. In addition, in a rodent model of hypertension, oral administration of a smooth muscle myosin inhibitor resulted in a sustained antihypertensive effect. Thus, the smooth muscle myosin inhibitor's preferential effect on renal blood flow makes this drug mechanism particularly appealing, because many patients with hypertension have renal insufficiency, and patients with heart failure could benefit from afterload reduction coupled with enhanced renal blood flow.

The northeast regional SPS meeting update: Safety pharmacology innovations and applications.

The Safety Pharmacology Society (SPS) held a Northeast (NE) regional meeting in Boston, MA on May 13, 2016 at the Vertex Pharmaceuticals Incorporated site. There were 103 attendees from the pharmaceutical industry, contract research organizations (CROs), academia, and global regulatory agencies. An assortment of scientific topics were presented by 7 speakers that included broad topics in the cardiovascular (organ on chip, statistical power and translation of rat cardiovascular telemetry data and dual inhibition of IKr and IKs on QT interval prolongation) and central nervous system (in vitro platform for neurotoxicity, an integrated risk assessment of suicidal ideation and behavior, and EEG advances in safety pharmacology) and a novel topic discussing preclinical challenges faced in the development of a novel gene therapy. A highlight of the meeting was an in-depth discussion on the fatty acid acyl hydrolase (FAAH) inhibitor BIA 10-2474 which involved a comprehensive overview of the biology and pharmacology of FAAH followed by a presentation from the Biotrial (Rennes, France) team that conducted the clinical trial. An additional poster session was held that included 13 fascinating posters on cutting edge safety pharmacology topics.

Smooth muscle myosin inhibition: a novel therapeutic approach for pulmonary hypertension.

OBJECTIVE: Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension. MATERIALS AND METHODS: Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline. RESULTS: CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%). CONCLUSION: Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.