Pharmacodynamics safety margin

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

Acute toxicity studies have been performed in various animals mice, rats, rabbits, cats, dogs, and macaques.18,20,35,36,40,44 Lethal doses of DMHP are extremely high, in comparison with the small doses required to produce its pharmacodynamic effects. For instance, the intravenous LD50 in mice is 63 mg/kg, whereas the minimal effective dose in 50% of the animals (MED50) is 0.075 mg/kg, for a safety factor of 840. The dose required to produce tranquilization in the unanesthetized dog is 0.05 mg/kg, and the minimal lethal dose is 10 mg/kg by the same route. The margin of safety in the dog is about 200. By comparison, the margin of safety of reserplne is 5.0. 

It is to be noted that the pharmacodynamics (PD) data (Fig. 12.19) clearly indicate that if DS-96 is to ever to find utility in the clinic as a LPS-sequestrant, it will have to be administered prior to the onset of sepsis, as a prophylactic, before the onslaught of the innate immune response. It is mandatory for a prophylactic regimen to have a very wide margin of safety and, consequently, we have paid particular attention to eliciting any potential toxicity ascribable to DS-96. Daily i.p. administration to rats at doses of 0, 5, and 10 mg/kg (free base equivalent) of DS-96 (either as TFA or HC1 salt the 10 mg/kg free base dose represents 10X 100% protective dose in mice on a body weight basis) for five days resulted in a dose-dependent... 

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