No abstract

Dalcetrapib targets cholesteryl ester transfer protein and increases high-density lipoprotein cholesterol (HDL-C) levels. It is in clinical development for the prevention of cardiovascular events and will likely be used in combination with standard of care, including statins. Three crossover studies in healthy males investigated the pharmacokinetic drug-drug interaction potential of 900 mg dalcetrapib and statins: two 3-period studies (dalcetrapib plus pravastatin or rosuvastatin) and a 2-period study (dalcetrapib plus simvastatin). Effect on lipids and safety were secondary end points. The 900 mg dose investigated is higher than the 600 mg dose currently being investigated in Phase III. Coadministration of dalcetrapib with pravastatin, rosuvastatin, or simvastatin was not associated with significant increases in statin exposure except for a 26% increase in rosuvastatin C(max) (90% CI 1.088 to 1.468) but not AUC(0-24) (90% CI 0.931 to 1.085). Dalcetrapib AUC(0-24) and C(max) were not significantly altered by coadministration with pravastatin, and were significantly lower when dalcetrapib was coadministered with rosuvastatin or simvastatin compared with dalcetrapib alone. The HDL-C increase with dalcetrapib was not compromised by coadministration with statins, and reduction in low-density lipoprotein cholesterol with dalcetrapib coadministered with statins was greater than with statins alone. Dalcetrapib alone and coadministered with statins was generally well tolerated.

The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT3 receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure-activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules.

The absence of clinically relevant effects of food, ranitidine or omeprazole on DNVr pharmacokinetics suggests that DNVr can be administered without regard to meals and in combination with H2 antagonists or proton pump inhibitors.

Coadministration of DNVr with MMT resulted in no significant pharmacokinetic interactions or signs of methadone withdrawal. No dosage adjustment is needed for MMT when coadministered with DNVr.