Drug development struggles with high costs and time consuming processes. Hence, a need for new strategies has been accentuated by many stakeholders in drug development. This study proposes the use of pharmacometric models to rationalize drug development. Two simulated examples, within the therapeutic areas of acute stroke and type 2 diabetes, are utilized to compare a pharmacometric model–based analysis to a t-test with respect to study power of proof-of-concept (POC) trials. In all investigated examples and scenarios, the conventional statistical analysis resulted in several fold larger study sizes to achieve 80% power. For a scenario with a parallel design of one placebo group and one active dose arm, the difference between the conventional and pharmacometric approach was 4.3- and 8.4-fold, for the stroke and diabetes example, respectively. Although the model-based power depend on the model assumptions, in these scenarios, the pharmacometric model–based approach was demonstrated to permit drastic streamlining of POC trials.

An analytical procedure for the simultaneous determination of pethidine and its N-Demethylated metabolite, norpethidine, in plasma is described. Pethidine and norpethidine are separated by partition chromatography, converted to the trichloroethyl carbamate with trichloroethyl chloroformate and determined by electron capture gas chromatography. The smallest amounts of pethidine and norpethidine determined by the method were 10 and 2 ng, respectively, in 0.1 ml plasma. The relative standard deviation in the determination of 50 ng of pethidine and 40 ng of norpethidine in 0.1 ml plasma wwere 5.8% (n = 8) and 6.3% (n = 10), respectively. The method was used to determine plasma levels of pethidine and norpethidine in three patients who received subcutaneous doses of pethidine 50-75 mg for postoperative pain. The peak levels of pethidine were found to be in the range 200-400 ng/ml, with a plasma half-life of the order of 4 hours. The levels of norpethidine were low.