Optimized Treatment of Refractory Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease or Heterozygous Familial Hypercholesterolemia With Alirocumab (OPTIMIZE).

Background: Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). In confirmatory trials, proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab substantially lowered LDL-C and reduced cardiovascular morbidity and mortality. However, the routine clinical use of alirocumab in Switzerland has not yet been studied.

Biorelevant Two-Stage In Vitro Testing for rDCS Classification and in PBPK Modeling-Case Example Ritonavir.

Biorelevant two-stage in vitro testing is increasingly used as a tool for various applications in drug development. Three important applications of two-stage in vitro testing are the classification of weakly basic drug compounds as part of the refined Developability Classification System, the prediction of intraluminal drug concentrations in the gastrointestinal tract and the prediction of plasma concentration profiles using physiologically based pharmacokinetic modeling. For the weakly basic, antiretroviral drug ritonavir, two-stage testing is triggered as a customized investigation in the refined Developability Classification System classification process to assess whether the drug could supersaturate and precipitate when exposed to the steep change in pH that occurs during drug transfer from the stomach into the small intestine.

Development, current applications and future roles of biorelevant two-stage in vitro testing in drug development.

Objectives: Various types of two stage in vitro testing have been used in a number of experimental settings. In addition to its application in quality control and for regulatory purposes, two-stage in vitro testing has also been shown to be a valuable technique to evaluate the supersaturation and precipitation behavior of poorly soluble drugs during drug development.

Key Findings: The so-called 'transfer model', which is an example of two-stage testing, has provided valuable information about the in vivo performance of poorly soluble, weakly basic drugs by simulating the gastrointestinal drug transit from the stomach into the small intestine with a peristaltic pump.

Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling.

The aim of this study was to optimize the in vitro transfer model and to increase its biorelevance to more accurately mimic the in vivo supersaturation and precipitation behaviour of weak basic drugs. Therefore, disintegration of the formulation, volumes of the stomach and intestinal compartments, transfer rate, bile salt concentration, pH range and paddle speed were varied over a physiological relevant range. The supersaturation and precipitation data from these experiments for Ketoconazole (KTZ) were coupled to physiologically based pharmacokinetic (PBPK) model using Stella® software, which also incorporated the disposition kinetics of KTZ taken from the literature, in order to simulate the oral absorption and plasma profile in humans.