A new cholesteryl ester (CE) transfer protein (CETP) inhibitor (CP-800,569) was evaluated. Doses of 30-1,800 mg were administered once daily to healthy subjects for 14 days. Serum CP-800,569 levels increased, and CETP activity decreased, in a dose-related manner. Serum levels of high-density lipoprotein (HDL) increased (by a maximum of 156%), and those of low-density lipoprotein (LDL) decreased (by a maximum of 47%). CP-800,569 also had the effect of lowering postprandial triglyceride levels. Trough concentrations of apolipoprotein E (apoE) increased: the maximum increases were 89% for total plasma apoE and 280% for HDL apoE. By contrast, the postprandial increases in total plasma levels of apoE and non HDL apoE were either diminished by CP-800,569 or reversed to decreases. CP-800,569 was very well tolerated, with some nonserious gastrointestinal adverse events seen only with the 1,800-mg dose. No changes in blood pressure (BP) were observed. The possible effects of higher CP-800,569 doses on aldosterone and cortisol levels could not be excluded. The results of this study may be useful in CP-800,569 dose selection.

5-{2-[4-(3,4-Difluorophenoxy)-phenyl]-ethylsulfamoyl}-2-methyl-benzoic acid (1) is a novel, potent, and selective agonist of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). In preclinical species, compound 1 demonstrated generally favourable pharmacokinetic properties. Systemic plasma clearance (CLp) after intravenous administration was low in Sprague-Dawley rats (3.2 +/- 1.4 ml min(-1) kg(-1)) and cynomolgus monkeys (6.1 +/- 1.6 ml min(-1) kg(-1)) resulting in plasma half-lives of 7.1 +/- 0.7 h and 9.4 +/- 0.8 h, respectively. Moderate bioavailability in rats (64%) and monkeys (55%) was observed after oral dosing. In rats, oral pharmacokinetics were dose-dependent over the dose range examined (10 and 50 mg kg(-1)). In vitro metabolism studies on 1 in cryopreserved rat, monkey, and human hepatocytes revealed that 1 was metabolized via oxidation and phase II glucuronidation pathways. In rats, a percentage of the dose (approximately 19%) was eliminated via biliary excretion in the unchanged form. Studies using recombinant human CYP isozymes established that the rate-limiting step in the oxidative metabolism of 1 to the major primary alcohol metabolite M1 was catalysed by CYP3A4. Compound 1 was greater than 99% bound to plasma proteins in rat, monkey, mouse, and human. No competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, P4502C9, P4502C19, P4502D6 and P4503A4 (IC50's > 30 microM) was discerned with 1. Because of insignificant turnover of 1 in human liver microsomes and hepatocytes, human clearance was predicted using rat single-species allometric scaling from in vivo data. The steady-state volume was also scaled from rat volume after normalization for protein-binding differences. As such, these estimates were used to predict an efficacious human dose required for 30% lowering of triglycerides. In order to aid human dose projections, pharmacokinetic/pharmacodynamic relationships for triglyceride lowering by 1 were first established in mice, which allowed an insight into the efficacious concentrations required for maximal triglyceride lowering. Assuming that the pharmacology translated in a quantitative fashion from mouse to human, dose projections were made for humans using mouse pharmacodynamic parameters and the predicted human pharmacokinetic estimates. First-in-human clinical studies on 1 following oral administration suggested that the human pharmacokinetics/dose predictions were in the range that yielded a favourable pharmacodynamic response.

Exposure‐response analysis of QT interval in clinical studies has been proposed as a thorough QT study alternative. Many exposure‐response model structures have been proposed for cardiovascular (CV) safety markers, but few studies have compared models across multiple drugs. To recommend preferred drug‐effect exposure‐response models on vital signs and electrocardiogram (ECG) intervals, an individual‐level model‐based meta‐analysis (39 studies and 1,291 subjects) compared 90 model structures. Models were selected to describe the data and cross‐validate studies on the same drug. The most commonly selected baseline model was an unstructured model (estimation of a value at each study nominal time) for all measures but blood pressure. The unstructured model estimated a better cross‐validated drug‐effect when considering all markers. A linear model was the most commonly selected to characterize drug‐effect on all markers. We propose these models as a starting point assisting with CV safety exposure‐response assessment in nondedicated small studies with healthy subjects.