Method development, levels correlation with clinical

In the approach described here method development is broken down into discrete stages as shown in Figure 1. The levels described are correlated with clinical and regulatory phases in Table 1 to provide rough guidance as to when in the pharmaceutical development process each level is applicable. 

DISTRIBUTION The distribution of 14C-pyridostigmine was studied by Birtley et al. Ten per cent of the i.m. dose was present in the alimentary tract within 1 h after injection and 0.3% of the dose is secreted in the bile. A high concentration of radioactivity occurred in the kidney when excretion in the urine was at its maximum level. Lower concentrations were present in the liver, intestinal contents, heart, blood, and muscle. Radioactivity was also detected in the lungs, spleen, and skin, but not in the brain, thymus gland, intestinal wall, or body fat. The detection of radioactive respiratory C02 suggested that to a small extent pyridostigmine may be metabolized by another route. The serum concentration was dose-dependent and was correlated with the clinical response. A radio-immunoassay (RIA) method was developed to determine the plasma concentration time profiles and tissue distribution of PB in rat following its i.m. administration. This study found that PB had a half-hfe (tl/2) of 25... 

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