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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. The evolution of the transfer model has resulted in various modifications of the experimental model set-up. Concomitantly, various research groups have developed simplified approaches to two-stage testing to investigate the supersaturation and precipitation behavior of weakly basic drugs without the necessity of using a transfer pump. Summary Given the diversity among the various two-stage test methods available today, a more harmonized approach needs to be taken to optimize the use of two stage testing at different stages of drug development.

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BackgroundLow-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.MethodsIn this prospective nation-wide cohort study, we aimed to investigate the patient profile and routine clinical efficacy and safety of alirocumab in 207 patients with ASCVD or heterozygous familial hypercholesterolemia and increased LDL-C despite maximally tolerated statin therapy. LDL-C was measured at baseline and after 3-months follow-up.ResultsOverall, mean age was 63 ± 11 years, 138 (67%) were men, and 168 (81%) had statin intolerance (SI). Patients with SI had a higher baseline LDL-C (4.3 ± 1.4 vs. 3.3 ± 1.4 mmol/l; p < 0.001) and less frequently ASCVD (71% vs. 95%; p = 0.002). After 3 months of treatment with alirocumab, LDL-C was reduced from 4.1 ± 1.5 to 2.0 ± 1.2 mmol/l (50.5%; p < 0.001). Mean absolute and relative reductions in LDL-C were similar in patients with vs. without SI (2.2 ± 1.2 vs. 1.9 ± 1.3 mmol/l; p = 0.24 and 49.0 vs. 56.6%; p = 0.11, respectively). In total, adverse events were recorded in 25 (12%) patients, with no new safety signals.ConclusionsIn routine clinical practice, alirocumab was predominantly used in patients with SI suggesting that the great majority of patients with insufficient LDL-C control who would be candidates for alirocumab are not receiving this therapeutic option in Switzerland. LDL-C lowering was potent and similar in patients with and without SI, replicating the favorable efficacy-safety profile of alirocumab from randomized trials.

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