Drug development

In the constantly changing world of drug development, it is important to have access to state-of-the-art techniques to study the physiological effects of the drug. For studies involving microcirculation and/or endothelial function, Perimed’s instruments are valuable additions to your medical device park.
Both for clinical and preclinical studies, Perimed’s products are used by contract research organizations (CRO’s) around the world. This can vary from studying cerebral blood flow in rodent models to microcirculatory function in human skin and everything in between.

Microcirculation imaging

PeriCam PSI, based on the Laser Speckle Contrast Analysis (aka LASCA or LSCI), is a powerful tool for studying microcirculation in real time. It both visualizes and quantifies the perfusion in the tissue with a high resolution and frame rates up to over 100 images/second. This enables studying dynamic responses in real time including 2-dimensional responses such as a flare reaction.

Case example: Target engagement biomarkers

Dorien Bamps, Center for Clinical Pharmacology, Leuven, Belgium.


At the Center for Clinical Pharmacology, an academic research organization located in the University Hospital of Leuven, we focus on the conduct of early clinical development trials. Unfortunately, in this area of research, attrition rates are extremely high, hampering the development of novel medicines. These high attrition rates are mainly due to a lack of efficacy in the target populations as animal models are often insufficient to predict target engagement in patients. Therefore, we specialize in the development of so called "target engagement biomarker models", in particular for the transient receptor potential (TRP) ion channel superfamily, which are appealing targets for the development of new generation analgesic drugs. Not only do these models provide insight in the pathophysiology underlying central nervous system diseases, they are also useful to give a first indication of target engagement in early clinical trials.

An ideal target engagement biomarker enables an objective read-out of the interaction between a drug and its target, is non-invasive, safe and easy-to-use. Measuring changes in dermal blood flow provides such a non-invasive way to assess target engagement in vivo, in human, with minimal risk for the subject. By applying a selective agonist of, for example, TRPV1 or TRPA1 to the skin of a subject’s forearm, we activate the specific TRP channel, expressed on the peripheral nerve endings of sensory neurons innervating the skin. As a result, sensory nerve fibers are activated which induces the local release of pro-inflammatory neuronal mediators. Some of these mediators, including calcitonin gene-related peptide (CGRP), will in turn act on vascular smooth muscle cells to produce vasodilatation. As both LDI and LSCI are non-invasive methods to measure this vasodilatory response induced by the topically applied agonists, they are ideal to evaluate in human target engagement with minimal risk or discomfort for the subject. As such, we use these techniques on a daily basis in both academic research as well as in the context of commercially sponsored clinical trials.

Development of the capsaicin model for TRPV 11:

Van der Schueren BJ, de Hoon JN, Vanmolkot FH, Van Hecken A, Depre M, Kane SA, De Lepeleire I, Sinclair SR. Reproducibility of the capsaicin-induced dermal blood flow response as assessed by laser Doppler perfusion imaging. Br. J. Clin. Pharmacol. 2007;64:580–590.

Development of the cinnamaldehyde model for TRPA12:

Buntinx L, Chang L, Amin A, Morlion B, de Hoon J. Development of an in vivo target-engagement biomarker for TRPA1 antagonists in humans. Br. J. Clin. Pharmacol. 2017;83:603–611.

Example of studies using the capsaicin model3:

Monteith D, Collins EC, Vandermeulen C, Van Hecken A, Raddad E, Scherer JC, Grayzel D, Schuetz TJ, de Hoon J. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers. Front. Pharmacol. 2017;8:740. de Hoon J, Van Hecken A, Vandermeulen C, Yan L, Smith B, Chen JS, Bautista E, Hamilton L, Waksman J, Vu T, Vargas G. Phase I, Randomized, Double-blind, Placebo-controlled, Single-dose, and Multiple-dose Studies of Erenumab in Healthy Subjects and Patients With Migraine. Clin. Pharmacol. Ther. 2018;103:815–825.

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See references

References

  • Reproducibility of the capsaicin-induced dermal blood flow response as assessed by laser Doppler perfusion imaging. Van der Schueren BJ, de Hoon JN, Vanmolkot FH, Van Hecken A, Depre M, Kane SA, De Lepeleire I, Sinclair SR. Br. J. Clin. Pharmacol. 2007;64:580–590.    
  • Development of an in vivo target-engagement biomarker for TRPA1 antagonists in humans. Buntinx L, Chang L, Amin A, Morlion B, de Hoon J. Br. J. Clin. Pharmacol. 2017;83:603–611.    
  • Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers. Monteith D, Collins EC, Vandermeulen C, Van Hecken A, Raddad E, Scherer JC, Grayzel D, Schuetz TJ, de Hoon J.Front. Pharmacol. 2017;8:740.    
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