Drug development clinical trials

Shi MM et al. Pharmacogenetic Application in Drug Development and Clinical Trials. Drug Metabolism Disposition 2001 29 591-595. 

While several P-gp inhibitors have entered clinical trials, the development of specific MRP inhibitors is still in its infancy. Similar to P-gp, various MRP inhibitors are already known— among others MK-571 [98-100], probenecid [101], ritonavir [102], leukotriene C4 [103], gemfibrozil [104], pyrrolpyrimidines [105], sulindac [106], and certain isothiocyanates [107], but their potential as auxiliary agents for oral drug delivery has to be further investigated. 

Also according to the drug label, in brief, 3-week controlled clinical trials, patients developed hallucinations, disorientation, anxiety, depression, psychomotor retardation (mental and physical slowing), depersonalization, disinhibition, euphoric mood, mood swings, and stress symptoms. Hallucinations were reported in 4% of the Ambien patients and none of the placebo patients. 

Szymkowski, D. E. (1996) Developing antisense oligonucleotides from the laboratory to clinical trials. Drug Discovery Today 1,415 428. 

This chapter endeavors to show that a population PK/PD approach to the analysis of count data can be a valuable addition to the pharmacometrician s toolkit. Nonlinear mixed effects modeling does not need to be relegated to the analysis of continuously valued variables only. The opportunity to integrate disease progression, subject level covariates, and exposure-response models in the analysis of count data provides an important foundation for understanding and quantifying drug effect. Such parametric models are invaluable as input into clinical trial and development path simulation projects. 

For the past few years, however, there has been a hiatus in the pace of discovery of novel medicinal agents. It has been postulated by some that the field has now slowed down due to the limitations of the almost strictly empirical approach that has been applied to date to drug development. It is possible, too, that the higher standards of efficacy and safety that a new drug must meet today, combined with the enormously increased costs of clinical trials, have acted to keep all but the most promising new drugs off the market. 

Leptin has proved to be an efficient treatment for the rare form of obesity associated with leptin deficiency. By contrast, the results of the fust clinical trial with human leptin in obese patients (without leptin deficiency) were less promising. This may be explained by leptin resistance in a high proportion of these patients. However, the mechanisms involved in the development of leptin resistance could become new drug targets. 

Apart from these two Vertex compounds, only one other caspase inhibitor, BDN-6556, has been used in clinical trials. This compound belongs to the class of oxamyl dipeptides and was originally developed by Idun Pharmaceuticals (taken over by Pfizer). It is the only pan-caspase inhibitor that has been evaluated in humans. BDN-6556 displays inhibitory activity against all tested human caspases. It is also an irreversible, caspase-specific inhibitor that does not inhibit other major classes of proteases, or other enzymes or receptors. The therapeutic potential of BDN-6556 was first evaluated in several animal models of liver disease because numerous publications suggested that apoptosis contributes substantially to the development of some hepatic diseases, such as alcoholic hepatitis, hepatitis B and C (HBV, HCV), non-alcoholic steato-hepatitis (NASH), and ischemia/reperfusion injury associated with liver transplant. Accordingly, BDN-6556 was tested in a phase I study. The drug was safe and... 

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