Preclinical development phase

The use of capillary electrophoresis (CE) during the synthetic drug development is described from the preclinical development phase to the final marketed stage. The chapter comprises the determination of physicochemical properties, such as acid—base dissociation constants (pKJ, octanol—water distribution coefficients (logP), and analysis of pharmaceutical counterions and functional excipients. 

Devices that have long histories of reliability as stand-alone products may behave differently when associated with a biologic. Conversely, when a biologic is associated with a device, a variety of chemical, physical, or conformational modifications could occur and alter its biologic activity in some manner. In the preclinical development phase, proof-of-concept (POC) testing is used to make a preliminary efficacy determination and is often designed to generate safety data. 

In this context the term nonclinical is often used interchangeably with preclinical, particularly to define the preclinical studies performed after a product has advanced into the clinic (and thus is no longer in the preclinical development phase). Diverse studies are performed at different times to answer specific questions that only become relevant during particular phases of clinical development for example, carcinogenicity studies are done to answer questions that ultimately arise at the end of lifetime administration to patients. Based on the explicit objective of safety studies to reveal or exclude potential adverse effects before they occur in healthy subjects or patients, the term preclinical will be used throughout this book to highlight the importance of the data to be derived prior to the specific clinical phase they are designed to support. 

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. 

Product specification documents and analytical test methods—In preclinical development, these are important documents and they evolve along with the development phases. Drug substances and products for clinical trials are tested based on these documents, and so are the stability samples. It is critical to ensure that the analyst will perform the right tests against the right specifications with the correct version of the test method. Therefore a mechanism must be in place to control these documents. This can be done manually or with TIMS. A manually controlled system would require the analyst to sign out hard copies of the documents from a central location. After the testing is done, the analyst would have to return these controlled documents to the... 

Hartinger, C. G., Jakupec, M. A., Zorbas-Seifried, S., Groessl, M., Egger, A. Bergar, W. KP1019, A New Redox-Active Anticancer Agent - Preclinical Development and Results of a Clinical Phase I Study in Tumor Patients. Chem. Biodiversity, 5, 2140-2155 (2008). 

IND Filed / Phase I Clinical Trials Proposed for Preclinical Development... 

FIGURE 20.1. The pharmaceutical development process, viewed as four stages (discovery, preclinical development, clinical development, and NDA review) as well as the important post-market surveillance phase. 

Research (on medicines). Numerous definitions of research are used both in the literature and among scientists. In the broadest sense, research in the pharmaceutical industry includes all processes of medicine discovery, preclinical and clinical evaluation, and technical development. In a more restricted sense, research concentrates on the preclinical discovery phase, where the basic characteristics of a new medicine are determined. Once a decision is reached to study the medicine in humans to evaluate its therapeutic potential, the compound passes from the research to the development phase. 

The annual R D expenditure for biopharmaceuticals is around US 19-20 billion. There are estimated to be 2500 biopharmaceuticals in the discovery phase, 900 in preclinical trials, and 1600 in clinical trials. This represents 44% of all drugs in the development phase and 27% of all drugs in both preclinical and clinical trials. The most common target is cancer and monoclonal antibodies and vaccines have the largest amount of R D activities. 

Alzheimer s Disease The vaccine being tested contains a small protein called jS-amyloid (AjS). This protein forms abnormal deposits, or plaques, in the brains of people with Alzheimer s disease. Researchers believe that Kji deposition causes loss of mental function by killing the brain neurons. The strategy of Aji vaccination is to stimulate the immune system to clean up plaques and prevent further A deposits. Although preclinical and Phase I studies showed the potential of the vaccine, the Phase II clinical trial was halted because 15 of 360 patients developed severe brain inflammation. Further studies showed that the A did generate the desired... 

The first epithilone, a highly potent microtubule stabilizer, in advanced clinical development (Phase II) is ZK-EPO (ZK-219447), while fludelone is still in preclinical trials (cf. Chapter 4). 

Preclinical drug development involves understanding of dosage, formulation, and route of administration, typically in animal models, so that safe and effective doses for human administration can be estimated. The drug development phase extends from prechnical assessment through clinical testing. 

Antidepressants as analgesics are almost a closed book as far as preclinical and clinical development is concerned. TCAs are an old drug class, and because of the rather problematic side-effect profile, interest in developing new drugs from this class is small. BL-1834 (Bioglan Lab.) is an intranasal formulation of doxepine that is in clinical development (phase II) for the treatment of severe pain. In patents on novel monoamine reuptake inhibitors, pain is usually claimed as a possible indication, but depression and anxiety are mentioned as the primary indications in most cases, and we are not aware of novel... 

Lead optimisation is the synthetic modification of a biologically active compound, to fulfill all stereoelectronic, physicochemical, pharmacokinetic and toxicologic required for clinical usefulness (IUPAC). This phase begins with the first chemical lead or lead series selected for optimisation (i.e. the "lead series selected" milestone) and concludes with a decision for an optimized compound to enter preclinical development (i.e. the "pre-clinical candidate selected" milestone). This phase consists of testing of a compound to determine the chemical structure that has the optimum potency and selectivity for the target in question. The phase includes the search for backup compounds and may also include early ADME and toxicity evaluation. 

Synthesis of active ingredients Preclinical testing Formulations development Phase I, II, III, and IV clinical trials Clinical trials supplies manufacturing Clinical packaging... 

Pharmacokinetics is used in all the development stages of a drug from preclinical to Phase IV trials (see section 11.3). Legislation normally demands... 

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