Towards consensus practices to qualify safety biomarkers for use in early drug development.

Application of any new biomarker to support safety-related decisions during regulated phases of drug development requires provision of a substantial data set that critically assesses analytical and biological performance of that biomarker. Such an approach enables stakeholders from industry and regulatory bodies to objectively evaluate whether superior standards of performance have been met and whether specific claims of fit-for-purpose use are supported. It is therefore important during the biomarker evaluation process that stakeholders seek agreement on which critical experiments are needed to test that a biomarker meets specific performance claims, how new biomarker and traditional comparators will be measured and how the resulting data will be merged, analyzed and interpreted.

Coronary vasodilator reserve and Framingham risk scores in subjects at risk for coronary artery disease.

BACKGROUND: The relationship between coronary vasodilator reserve and risk of coronary heart disease (CHD) in subjects without coronary artery disease (CAD) is not well known. METHODS AND RESULTS: We studied 289 subjects (mean age, 58 +/- 10 years) without overt CAD and at low (< 10%) to intermediate risk (10%-20%) for CHD based on Framingham risk scores (RAMPART [Relative and Absolute Myocardial Perfusion changes as measured by Positron Emission Tomography to Assess the Effects of ACAT Inhibition: A Double-Blind, Randomized, Controlled, Multicenter Trial]). Coronary flow reserve (CFR) and coronary vascular resistance (CVR) were calculated from rest and adenosine nitrogen 13 ammonia positron emission tomography studies. Framingham-estimated CHD risk was used to as a surrogate for outcomes. Compared with subjects with low-risk scores (n = 150), those with intermediate-risk scores (n = 139) had a higher minimal CVR (49.3 +/- 17.41 mm Hg x mL(-1) x min(-1) x g(-1) vs 52.4 +/- 16.4 mm Hg x mL(-1) x min(-1) x g(-1), P = .05) and lower CFR (2.8 +/- 1.0 vs 2.5 +/- 0.8, P = .02). CFR was inversely related to CHD risk (R = -0.2, P = .006), and CVR was directly related to CHD risk (R = 0.2, P < .001). The mean CFR was significantly lower in patients in the first quartile of CHD risk compared with those in the fourth quartile (2.3 +/- 0.7 vs 2.8 +/- 1.0, P = .02), and the minimal CVR was significantly higher (44 +/- 15 mm Hg x mL(-1) x min(-1) x g(-1) vs 53 +/- 14 mm Hg x mL(-1) x min(-1) x g(-1), P < or = .05). CONCLUSIONS: In subjects without clinical CAD and at low to intermediate risk, CFR assessed by positron emission tomography is inversely related to estimated 10-year CHD risk.

Quantitative relation between hemodynamic changes during intravenous adenosine infusion and the magnitude of coronary hyperemia: implications for myocardial perfusion imaging.

OBJECTIVES: The goal of this study was to determine the relationship between changes in cardiac hemodynamics during intravenous adenosine (ADO) infusion, and myocardial blood flow (MBF). BACKGROUND: The relationship between changes in MBF and the peripheral hemodynamic effects during peak adenosine infusion is unknown. METHODS: We studied 348 (age 57 +/- 11 years; 106 females) without evidence of obstructive coronary artery disease by positron emission tomography (PET). Patients underwent [(13)N]ammonia PET imaging to measure MBF and coronary vascular resistance (CVR) at rest and during a standard 6-min ADO infusion. Changes in heart rate (HR) and mean arterial pressure (MAP) were measured at baseline and during peak hyperemia. RESULTS: During ADO, HR increased (delta: 24 +/- 11 beats/min) and MAP decreased (delta: -2 +/- 10 mm Hg). Overall, delta HR correlated poorly with hyperemic MBF (R = 0.10, p = 0.06) and with CVR (R = 0.11, p = 0.04). Delta MAP also showed a weak correlation with hyperemic MBF (R = 0.04, p = 0.44) and with CVR (R = 0.11, p = 0.04). Patients in the lowest tertile for delta HR showed a 7% lower hyperemic MBF (1.84 +/- 0.6 ml/min/g vs. 1.98 +/- 0.6 ml/min/g, p = 0.022) and an 8% higher CVR (54 +/- 20 mm Hg/ml/min/g vs. 50 +/- 17 mm Hg/ml/min/g, p = 0.056) compared with those in the highest tertile. Patients in the lowest tertile for delta MAP (i.e., greatest decline) showed similar hyperemic MBF, and an 8% lower CVR compared with those in the highest tertile (p = NS for both). These small differences between tertiles remain, even after adjusting for differences in age, gender, smoking status, and lipid profile. CONCLUSIONS: Changes in cardiac hemodynamics during intravenous ADO are generally poor predictors of changes in MBF and CVR during peak hyperemia, and, thus, they should not be used to assess the effectiveness of vasodilator stress in myocardial perfusion imaging.

Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions.

BACKGROUND: Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis. METHODS AND RESULTS: This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level <125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was approximately 200 mm3, and the least squares mean change at end of treatment was 0.7 mm3 for placebo and 7.7, 4.1, and 4.8 mm3 for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted P=0.17 [unadjusted P=0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (P=NS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups (P<0.05 in all groups). CONCLUSIONS: Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in LDL cholesterol.