On the 18th of April, Titia Ruijs successfully defended her PhD thesis at Leiden University. In her thesis, Titia describes the potential of three measures of excitability to detect pharmacodynamic effects of ion channel modulators: transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG), nerve excitability threshold tracking (NETT), and muscle velocity recovery cycles (MVRC).
Abnormalities in cell excitability can be found in multiple neurological and neuromuscular disorders, such as epilepsy, amyotrophic lateral sclerosis (ALS) and myotonia congenita. Excitability is driven by voltage- and neurotransmitter-gated ion channels. Pharmacological modulation of these ion channels is therefore promising as treatment for excitability-related diseases. In early phase drug development, the use of biomarkers for pharmacodynamic effects in healthy subjects and first-in-patient studies is pivotal. In this thesis, TMS-EMG/EEG was used to evaluate effects on cortical excitability; NETT to assess peripheral nerve excitability; and MVRC to explore muscle cell excitability. Firstly, these measurements were tested in proof-of-concept studies using registered drugs known to influence excitability. These studies were used to explore if the measurements are sensitive to drug-induced changes in excitability, and the test-retest variability and feasibility to apply them in the context of a clinical study in healthy subjects were evaluated. After validation of the methods, the measurements were used in early phase clinical drug studies with novel drug candidates. In the discussion the implications of the findings for use of these methods as biomarkers in future drug development programs is discussed: an evaluation of their general value as pharmacodynamic biomarkers for ion channel modulators; their feasibility for use in early phase drug studies; and finally, ideas for future research.
Read Titia’s thesis here.
