PK effects of ethanol-drug interactions can easily be obtained using the BrEC guided method by comparing the amounts of ethanol infused between drug and placebo. This resulted in an ideal method to study the pharmacodynamic CNS effects of constant serum ethanol concentrations concomitantly

Highlights

  • Pseudo-steady state conditions can be maintained for hours
  • Different ethanol concentration set-points
  • Suitable for interaction studies with CNS-active drugs
  • Easy to incorporate in clinical trials
  • Validated in both Caucasian and Japanese subpopulations, in men and women, in elderly and obese subjects, and in patients.

Summary

CHDR has developed and validated an accurate intravenous infusion procedure. Online 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 will instantly adapt when a drug modifies ethanol kinetics

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 (hypnotics/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 allowed the best possible interpretation of drug-ethanol interactions for a wide range of different drug classes. A recent example is a first in class treatment for insomnia using our EthanolClamp, which clearly showed additive effects on some attention and sedation tasks, but excluded less predictable and hence more problematic supra additive effects.

Driving under influence

EMA guidelines suggest that drugs with sleep-enabling properties are tested for their effect on driving and operating machinery. The EthanolClamp can be used as a suitable positive control and set to regional driving limits e.g. most of the EU 0.05% (0.5 g/L) or many US states 0.08%. The EthanolClamp has been used together with the NeuroCart and driving simulators for this purpose.

Positive control

Essential tremor (ET) is a highly prevalent neurological condition, for which no specific treatments have been developed. About half of all ET patients report tremor reduction after drinking alcohol. CHDR’s EthanolClamp was used as a positive control, early during the development of two novel anti-tremor treatments. 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 – which both unfortunately 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

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