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The administration of insulins by subcutaneous injection is nowadays widely prevalent. The injection site is located below the dermis and composed of cells and the extracellular matrix formed of a network of macromolecules such as hyaluronic acid and collagen. Following an injection, the insulins from the formulated products are timely released as drug molecules from the injection site into systemic circulation. In this publication, we show the development of an in vitro setup utilizing a hydrogel composed of a special collagen-hyaluronic acid mixture that mimics the extracellular matrix. Another setup was used for differentiation of the commercially available and research insulin formulations by determining the in vitro permeation characteristics with the results that were correlated with the human in vivo data. Significant differentiation was achieved at 90 % confidence level between the permeation curves of insulin glulisine containing formulations (U100 and a concentrated research formulation), while in case of the insulin lispro containing formulations (U100 and U200) the permeation curves showed similarity. These results demonstrated that the in vitro setup may be used as a tool for formulation development and drug candidate profiling as it is able to differentiate or show similarities between the agglomeration states and concentration of the active pharmaceutical ingredients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Alirocumab undergoes target-mediated clearance via binding of proprotein convertase subtilisin/kexin type 9 (PCSK9). Statins increase PCSK9 levels; the effects of nonstatin lipid-lowering therapies are unclear. Every-4-weeks dosing of alirocumab may be appropriate for some patients in absence of background statin but is not yet approved., Methods and Results: Low-density lipoprotein cholesterol (LDL-C), PCSK9, and alirocumab levels were assessed in subjects (LDL-C >130 mg/dL, n=24/group) after a 4-week run-in taking oral ezetimibe, fenofibrate, or ezetimibe placebo, when alirocumab 150 mg every 4 weeks (days 1, 29, and 57) was added. Maximal mean LDL-C reductions from day -1 baseline (prealirocumab) occurred on day 71 in all groups: alirocumab plus placebo, 47.4%; alirocumab plus ezetimibe, 56.6%; and alirocumab plus fenofibrate, 54.3%. LDL-C reductions were sustained through day 85 with alirocumab plus placebo (47.0%); the duration of effect was slightly diminished at day 85 versus day 71 with ezetimibe (49.6%) or fenofibrate combinations (43.2%). Free PCSK9 concentrations were lowest at day 71 in all groups, then increased over time; by day 85, free PCSK9 concentrations were higher, and alirocumab levels lower, with alirocumab plus fenofibrate, and to a lesser extent alirocumab plus ezetimibe, versus alirocumab plus placebo., Conclusions: Alirocumab 150 mg every 4 weeks produced maximal LDL-C reductions of 47% in combination with placebo and 54% to 57% in combination with ezetimibe or fenofibrate. The oral lipid-lowering therapies appear to increase PCSK9 levels, leading to increased alirocumab clearance. Although the duration of effect was modestly diminished with alirocumab plus ezetimibe/fenofibrate versus placebo, the effect was less than observed in trials with background statins, and it would not preclude the use of alirocumab every 4 weeks in patients taking these nonstatin lipid-lowering therapies concomitantly., Clinical Trial Registration: URL: http://www.Clinicaltrials.gov. Unique identifier: NCT01723735., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Cathepsin A (CathA) is a lysosomal protein where it forms a stable complex with neuraminidase and ß-galactosidase. CathA also has enzymatic activity and is involved in the degradation of many peptides. CathA was recently discovered as a target for heart failure, fostering the development of CathA inhibitors with SAR164653 as a frontrunner. The first-in-man study investigated single oral doses from 20 to 800 mg of SAR164653 followed by repeat dose studies at doses up to 800 mg in healthy young and elderly subjects. SAR164653 was safe and well tolerated at doses up to 800 mg in healthy subjects, and a maximum tolerated dose could not be determined from the study. Activity of ß-galactosidase measured in leukocytes did not show any abnormalities. The tmax was 1.0 to 2.5 hours, and the t1/2 was ∼5-11 after single dosing; exposure increased less than dose proportional. Following multiple dosing, accumulation was not observed, Cmax and AUC0-24 increased in a dose-proportional manner, and t1/2 was around 14-20 hours. The novel CathA inhibitor SAR164653 was found to have a favorable safety profile in these early phase 1 studies, but further studies are required to confirm if SAR164653 is equally safe in patients undergoing long-term treatment., (© 2015, The American College of Clinical Pharmacology.)

Aims: We investigated the relative pharmacokinetics, pharmacodynamics, and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab following injection at three different sites., Methods: Sixty healthy subjects (39 male, 21 female; age 20-45 years) were randomized to receive a single subcutaneous injection of alirocumab 75 mg via 1-mL prefilled pen into the abdomen, upper arm, or thigh (NCT01785329). Subjects were followed for 85 days ± 2 days following study drug administration. Pharmacokinetic (PK) parameters for the systemic exposure of alirocumab were calculated, and levels of free PCSK9 were assessed. Percentage changes from baseline in LDL-C were compared between injection site groups using linear mixed-effects models., Results: Alirocumab concentration-time profiles were similar, and free PCSK9 levels were reduced to approximately zero between Day 3 and Day 4 postinjection in all groups. LDL-C levels reached nadir on Day 15 postinjection in all groups with mean percentage reductions of 48.4% (abdomen), 39.5% (upper arm), and 45.6% (thigh) at this time point. A similar effect on LDL-C levels was seen across the entire time course of the study at all three injection sites. Treatment-emergent adverse events were experienced by 8/20 (abdomen), 11/20 (upper arm), and 13/20 (thigh) subjects. There were 2 mild/transient injection site reactions. There were no serious adverse events., Discussion: A single subcutaneous administration of alirocumab 75 mg via prefilled pen was well tolerated with similar pharmacokinetics and pharmacodynamics when injected into the abdomen, upper arm, or thigh., Conclusion: These results suggest that alirocumab can be interchangeably injected in the abdomen, upper arm, or thigh., (© 2014 Sanofi and Regeneron Pharmaceuticals Inc. Cardiovascular Therapeutics published by John Wiley & Sons Ltd.)

Background: Dried blood spot (DBS) sampling could potentially become the preferred blood collection technique in toxicological and clinical studies. Autoradiography was performed to study compound distribution within a dbs under different conditions using five papers, 31ETF, Grade 226, 903(®), FTA(®) and FTA(®) Elute., Results: The results showed an uneven distribution in all papers with common distribution patterns regardless of compounds: decreased concentrations along the edge, the volcano effect in the middle and the speckle pattern in the center. Treated papers were more readily influenced by environmental factors., Conclusion: Autoradiography enables visualization of a compound's distribution and can guide bioanalytical assay development by allowing convenient evaluation of factors, such as choice of paper, spotting volume, punch size, punch location, temperature and humidity.

Objectives: AVE0118 is a novel blocker of the K(+) channels K(v)1.5 and K(v)4.3 which are the molecular basis for the human cardiac ultrarapid delayed rectifier potassium current (I(Kur)) and the transient outward current (I(to)). The objective of this study was to investigate the effect of AVE0118 on atrial refractoriness (ERP), left atrial vulnerability (LAV) and on left atrial monophasic action potentials (MAP) in pentobarbital anesthetized pigs in comparison to the selective I(Kr) blocker dofetilide in order to assess the therapeutic potential of the novel K(+) channel blocker for atrial fibrillation., Methods: Atrial ERP was determined with the S1-S2-stimulus method in the free walls of left and right atrium at 240, 300 and 400 ms basic cycle length (BCL). The inducibility of mostly nonsustained atrial tachyarrhythmias by the premature S2 extrastimulus, which is very high in the left pig atrium and referred to as LAV, was evaluated before and after drugs. Left atrial epicardial MAP was recorded to study the influence of the potassium channel blockers on the time course of repolarization. Left ventricular epicardial MAP, ERP and QT interval were measured to investigate a possible effect of AVE0118 on ventricular repolarization., Results: ERPs determined at 240, 300 and 400 ms BCL were significantly shorter in the left vs. right atrium (99+/-3, 106+/-4 and 113+/-3 ms vs. 133+/-4 ms, 142+/-4 and 149+/-5, respectively; p<0.001; n=21). AVE0118 administered i.v. dose-dependently prolonged the atrial ERP independent from rate and inhibited LAV (100% at 0.5 and 1 mg/kg) while having no effect at all on the corrected QT (QTc) interval. At 1 mg/kg (n=5) AVE0118 prolonged left vs. right atrial ERP by 49.6+/-4.1 ms vs. 37.7+/-9.7 ms (means+/-SEM of changes at 240, 300, and 400 ms BCL), respectively, corresponding to a relative increase of 53.2+/-6.2% vs. 27.6+/-6.8% (p<0.05 for percent increase of left vs. right atrial ERP). In a separate group of pigs (n=5) AVE0118 had no effect on left ventricular ERP at 333, 400 and 500 ms BCL and no effect on MAP duration and QT at 600 ms BCL. After 1 mg/kg of AVE0118 the atrial MAP was significantly prolonged already at 10% repolarization (P<0.05; n=7) reaching the maximum at 40% repolarization. In contrast to AVE0118 the effect of dofetilide (10 microg/kg) on atrial MAP started to become significant only at 60% repolarization (n=6) with a maximum increase at 90%. Dofetilide, which prolonged the QTc interval by 16.9% (P<0.001), had a significantly stronger effect on right (34.7+/-5 ms) vs. left atrial ERP (23.5+/-7 ms) at 300 ms BCL, respectively, but did not significantly inhibit LAV (14%; n=6)., Conclusion: The novel K(+) channel blocker AVE0118 prolonged atrial ERP and showed strong atrial antiarrhythmic efficacy with no apparent effect on ventricular repolarization in pigs in vivo.