Maximum tolerated dose principle

As industry sought to develop new, safer and more specific pesticides for agricultural use, toxicology studies became more elaborate, sophisticated and more sensitive. Toxicokinetic principles were used too infrequently in setting doses for subchronic and chronic studies. Maximum tolerated doses used in these tests may have well exceeded the metabolic capacity of the test animal. 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

Dose A high, supratherapeutic dose of the NCE, which results in plasma levels in excess of what would be observed in patients with impaired clearance of the drug, should be used in the TQT study. The E14 states If not precluded by consideratimis of safety or tolerability due to adverse effects, the drug should be tested at substantial multiples of the anticipated maximum therapeutic exposure. The overriding principle is that plasma levels achieved with the supratherapeutic dose should exceed the worst-case scenario in patients, taking into account both intrinsic (e.g., renal impairment) and extrinsic factors (e.g., drug interactions). As an example, for NCEs that are CYP 3A4 or 2D6 substrates, the achieved exposure must exceed that observed with concomitant administration with potent 3A4 inhibitors, and in 2D6 poor metabolizers (Abbas et al. 2012 Boyce et al. 2012 Chaikin et al. 2005 Dalen et al. 2010 Malhotra et al. 2007 Robert et al. 2007 Tyl et al. 2012 Zhu et al. 2010). For a renally cleared drug, plasma levels that are only... 

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