Exploratory development tolerability

The term exploratory development (ED) can be defined as the first part of clinical drug development in which tolerability, pharmacokinetics and pharmacodynamic activity are defined in man and in which an early indication of therapeutic efficacy is often obtained . A new active substance (NAS) can be defined as an unlicensed new chemical or biological entity with activity in biological systems whose therapeutic potential is under investigation . The overall aim of ED should be to select appropriate NASs for full development (ED) and to reject those that will not make useful medicines, as early as possible. 

Similar to LSD and other monoamine hallucinogens, mescaline suppresses locomotor and exploratory behavior in novel environments (Wing et al. 1990). Also similar to LSD, tolerance develops to the behavioral effects of chronic doses of mescaline (Murray et al. 1977). Mescaline increases aggression in rat models (Sbordone et al. 1978) however, this is an elicited aggression (by electric shock) and does not necessarily generalize to human behavior. Increased aggression is not characteristic of humans using mescaline. 

The first tolerability studies in early clinical development always provide pharmacokinetic (PK) data over a considerable dose range. Especially the explorative first-in-man study with escalating single doses, or an explorative proof of principle study with escalating multiple doses provides a valuable basis for an exploratory assessment of dose linearity/ proportionality of drugs in humans. In addition such an assessment can directly help within the same study to optimize the dose selection and dose progression. Already in this early phase of the development, these data are going to support exposure-response relationships, and thus a potential submission (US FDA 2003, ICH E4 1994). 

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