Phase 1, preclinical development programs

Improvement of sensitivity of the bioanalytical method is often needed to support PK evaluation of drug candidate during clinical development. This sensitivity requirement is mainly due to the fact that the phase I doses are usually much lower than the doses administrated during the preclinical development phase. An HPLC-MS/MS method had been validated in rat, dog, and mouse plasma for support of a preclinical development program. A summary of the validation parameters in rat plasma are given in Table 8.8. 

Pharmaceutical sponsors now frequently conduct in vitro studies in the preclinical phase of drug development programs to assess the contribution of CYP or other enzymes to the metabolic elimination of an investigational drug and the ability of an investigational drug to inhibit specific metabolic pathways. The utility of these studies has been enhanced by the availability of specific enzyme preparations, microsomal preparations, and liver cell preparations, together with... 

The drug development program is divided into preclinical development, clinical development, and post-approval surveillance. Several preclinical and clinical trials are conducted during this program. In the following the phases of the clinical drug development process are described with a special focus on the data available for modeling and simulation and some objectives are exemplarily listed for the respective phases. 

Plan strategically. The entire integrated development program should be planned early, to identify when each clinical phase will require the supportive preclinical information. Critical decision points must be identified and these decisions made in a timely fashion. A strategy must be planned to address potential issues, such as lack of a relevant species or changes to the product or manner of use. 

From the first time a promising molecule is identified. in a drug discovery and screening program to the time it enters a first-in-human Phase I clinical trial, an enormous amount of scientific work and evaluation must be performed. Preclinical development, as defined in this chapter, encompasses all of the activities that must take place before a new chemical entity can be administered to humans. As such, it spans the gap between drug discovery and clinical testing. 

Early development work utilized free base 2 in some preclinical toxicology and early Phase I clinical studies. As the development program progressed, 2 was found to have unacceptably slow filtration properties, making its large-scale isolation unattractive. For instance, filtration of 13 kg of 2 required 8 h for a 2" cake on a 4 Nutsche filter. A salt-screening exercise was undertaken in an effort to quickly identify a crystalline and pharmaceutically acceptable salt of 2 for commercialization. 

If the preclinically devised label text is the esoteric goal of the clinical development program, the operational aspect of the program is dictated by need for clinical trial subject safety. The traditional terminology divides the program into four temporally related phases. There are well-established definitions of these phases ... 

After optimization, scientists test the lead compounds in more sophisticated models including pharmacokinetics, pharmacodynamics, and toxicity. The optimal molecule selected from these assessments is then declared a new dmg candidate and moves on to the next phase (development). If a program is successful, it may take a total of 3-6 years from target selection and validation through lead generation, lead optimization, and preclinical evaluation in animals to candidate selection for a potential new medicine. 

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