Highlights
- Our ethanol clamping procedure is validated in Caucasian and Japanese subpopulations, in men and women, in elderly and obese subjects, and in patients.
- Using ethanol clamping, pseudo steady-state conditions can be maintained for hours.
- Ethanol concentration set-points can be adjusted according to breath ethanol concentrations (BrEC).
- Ethanol clamping is suitable for interaction studies with CNS-active drugs.
- The EthanolClamp can be easily incorporated in clinical trials.
Summary
CHDR's EthanolClamp is a validated and accurate intravenous ethanol infusion procedure. Real-time individual adjustments in infusion rates are made using breath ethanol samples (BrEC) as a guideline to achieve a pseudo steady-state ethanol level. The BrEC-guided method instantly adapts when a drug modifies ethanol kinetics. Ethanol clamping can induce significant pharmacodynamic effects in a wide range of CNS domains.
Interaction studies with CNS-active compounds
Guidelines from the FDA and EMA recommend that investigational medicinal products (IMPs) being developed for the treatment of insomnia, such as hypnotics or sedatives, are tested in combination with alcohol (ethanol) for possible interactions. This can be difficult because of ethanol’s variable kinetic and dynamic properties. CHDR’s EthanolClamp largely eliminates this variability, and has already enabled optimal interpretation of drug-ethanol interactions for a wide range of different drug classes. For example, in a recent study of a first-in-class treatment for insomnia involving EthanolClamp, the data clearly showed additive effects of ethanol on some attention and sedation tasks, but excluded less predictable and hence more problematic supra-additive effects.
Driving under the influence
EMA guidelines suggest that drugs with sleep-inducing properties are tested for their effects on driving and operating machinery. The EthanolClamp can be used as a suitable positive control. The infusion rate can be set to reach regional driving limits, such as 0.05% (0.5 g/L) as in most of the EU, or 0.08% as in many US states. The EthanolClamp has been used together with the NeuroCart and driving simulators for this purpose.
Positive control in essential tremor patients
Essential tremor (ET) is a highly prevalent neurological condition, for which no specific treatments have been developed. Meanwhile, about half of all ET patients report tremor reduction after drinking alcohol. In the early stages of the development of two novel anti-tremor treatments, CHDR’s EthanolClamp was used as a positive control. In both cases, stable levels of ethanol caused a highly significant suppression of tremors in only a small number of ET patients. This provided a meaningful effect level for clinically significant effects of the two new novel drugs – both of which ultimately had much less effect than ethanol.
Our EthanolClamp can also provide a functionally relevant benchmark to determine the clinical relevance of drug-induced CNS depression.
