Suritozole

Unless it is carefully controlled, bias often distorts the results of clinical trials, usually exaggerating the magnitude of true efficacy. For that reason, procedures to limit bias have been mandated by the FDA when assessing efficacy in clinical trials. The present review shows that the effects of bias in preclinical studies are at least as large as in clinical trials, and since bias is not usually controlled in preclinical proof of concept studies, compounds that actually have little or no therapeutic potential may often be advanced into clinical trials. This possibility is supported by the fact that lack of efficacy is the single biggest reason why compounds fail in the clinic. The shift to target-based discovery during the last 10-15 years may have further increased the effects of bias on preclinical assessments of potential efficacy, and contributed to the continuing decline in clinical success rates. Procedures are available to control for bias during preclinical assessments of potential efficacy, and their use could dramatically increase clinical success rates and substantially reduce the costs of drug discovery and development.

MDL 26479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimer's disease. As part of a dose tolerance trial, the single- (SD) and multiple-dose (MD) pharmacokinetics of MDL 26479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26479 concentrations were determined by HPLC. Plasma MDL 26479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230-fold SD range from 0.5 to 3.8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52.9 to 13.8 Lh-1. MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half-life estimates were similar and independent of dose.