Clinical phases

The partition coefficient and aqueous solubility are properties important for the study of the adsorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) of drugs. The prediction of the ADME-Tox properties of drug candidates has recently attracted much interest because these properties account for the failure of about 60 % of all drug candidates in the clinical phases. The prediction of these properties in an early phase of the drug development process could therefore lead to significant savings in research and development costs. 

Only three dalbaheptides are commercialized vancomycin (39) and teicoplanin (18—22) for human health, and avoparcin (63—65) for animal usage. Vancomycin, the main trademark of which is EH Lilly s Vancocin had 1990 sales around 160 million. Total annual production is in the vicinity of 8 t. Teicoplanin, trademarked Targocid, had 1990 sales of 35 million corresponding to 200 kg. Teicoplanin is commercialized in Europe, Hong Kong, Korea, and the Middle East. It is at the late developmental clinical phase in North America and Japan. Avoparcin is used as a growth promoting feed additive (see... 

Dtugs in clinical development that directly target the A(3 pathway are at an early stage. Inhibitors of (3- and y-secretases that can lower the A 3 production have entered clinical phase trials with (3-secretase inhibitors being years behind the development of y-secretase inhibitors. Functional y-secretase inhibitors have been shown to reduce the rate of A 3 formation in vitro and in vivo. The reduction of A 3 monomer levels could prevent oligomer formation and subsequent syn-aptotoxicity. Numerous anti-amyloid approaches to... 

OPG has been shown to reduce bone turnover in postmenopausal women. More recently, Denusomab, an anti-RANKL mAb, has been tested for its ability to increase BMD and to reduce bone turnover. Results were promising and clinical phase III studies with fracture endpoints are presently under way. 

Receptor Company Clinical phase Compound Indication Status... 

The majority of non-clinical studies are undertaken in the pre-clinical phase of drug development. These studies serve both to guide the developer and satisfy the regulatory authorities. The objectives of this phase can be summarised as follows ... 

Safety and quality aspects are the main topics that must be addressed from a regulatory perspective at the pre-clinical phase of drug development. Indicative efficacy data will also be obtained, but authoritative data can be obtained only from clinical studies conducted with humans. Safety and preliminary efficacy indications... 

In addition to the safety studies, extensive investigations must be undertaken to establish the quality of the drug substance and product(s) during the pre-clinical phase. These will usually commence with drug discovery, where the initial characterisation of... 

In a clinical phase II trial, the efficacy of varions doses of pegylated IFN-a2a (90-270 pg weekly) administered for 24 weeks was studied in treatment-naive patients, by comparison with standard IFN-a2a at a dose of 4.5 MU three times a week... 

Liposomes have been studied to improve the ocular availability of drugs after application to the eye or after intravitreal injection. Besides, a liposomal eye drop formulation for the treatment of dry eye symptoms was developed and entered the clinical phase II stage (Guo et al., 1988). 

Gabizon A., Sulkes, A., Peretz, T., Druckmann, S., Goren, D., Amselem, S., and Barenholz, Y. (1989). Liposome-associated doxorubicin Preclinical pharmacology and exploratory clinical phase, in Liposomes in the Therapy of Infectious Diseases and Cancer. (G. Lopez-Berestein and I. J. Fidler, eds.), Alan R. 

Figure 22.2 Three different clinical phase II trials, each with slightly different end points, are compared on an eqnal footing. This comparison is made possible by nsing these diverse data to derive a single model with a nniform end point. It is clear that the maximum effect was approached in only one trial. Modeling and analysis of the data would likely have suggested phase II trials that included more data at higher doses.

However, pervasive computing will ultimately do much more it will change the very way in which new drugs are tested. At present, all drugs go through three clinical phases, but the process is both very costly and very inefficient. Clinical trials cannot detect rare side effects and drug interactions, or sometimes even fairly common reactions. In fact, one recent study conducted by Harvard Medical School and Public Citizen, the US consumer advocacy... 

HU-210 is (8.1) among the most potent cannabinoids known. Its enantiomer HU-211 (8.2) does not bind to the cannabinoid receptor and lacks psychotropic side effects (as long as optical purity is guaranteed). In animal models it shows analgesic and antiemetic activity. It also shows neuroprotec-tive effects after brain injury and was tested in humans as anti-traiuna agent, where it did not meet the expectations in a clinical phase III trial. 

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

Our whole task from a clinical perspective includes (1) delineation of the patterns of behavioral pathology induced both during the active stimulant abuse phase and the phases of withdrawal (2) description of the sequential profile of underlying structural and functional pathology at each of the clinical phases and (3) an attempt to elucidate the relationship between (1) and (2). In addition, an understanding of the pharmacological and other parameters sufficient and necessary for inducing components of the stimulant syndrome is clearly needed and can be obtained only from basic laboratory studies. 

There have been significant advances in the treatment of CML. The success of therapy depends in part on the clinical phase of the disease. Nearly all patients with CML are treated initially with imatinib. Hydroxyurea may be used after diagnosis to rapidly reduce high white blood cell (WBC) counts and to prevent complications associated with large numbers of circulating neutrophils. Imatinib also can reduce peripheral WBC counts over... 

The gold-standard assay used for all chemokine receptor inhibitors that reach clinical-phase trials is the chemotaxis functional assay. This assay relies on the ability of chemokines to recruit cells expressing their respective receptor to areas of inflammation. In vitro, this assay was first described in detail by Taub et al. (16) for 24/48-well plates currently, this can be achieved by using 96-well plates. Cells are incubated in the upper chamber with an antagonist for a particular receptor (at different concentrations or with buffer) and challenged to migrate to the lower chamber, which has the relevant chemokine. After 2 to 4 hours of incubation at 37°C, the upper chamber inlet is removed and the cells in the lower chamber quantified by fluorescence with, for example, Calcein AM (Invitrogen, Carlsbad, CA). 

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

Approval Phase Clinical Phase Preclinica Phase... 

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). 

Based on these findings and toxicology studies [233], human clinical phase I studies have been initiated [234]. In tumor biopsies from melanoma patients obtained after treatment, a reduction was found in both the specific mRNA (M2 subunit of ribonucleotide reductase, RRM2) and in the protein (RRM2) levels when compared to pre-dosed tissue. The presence of an mRNA fragment that... 

Clinical phase I and II data reveal arzoxifene to be safe, well tolerated, and efficacious. Two multi-institutional phase II trials including 100 women with metastatic or recurrent endometrial cancer have demonstrated significant activity of arzoxifene at 20 mg/d in patients with metastatic or recurrent endometrial cancer. The observed clinical response rates were 25 and 31%, with a mean response duration of 19.3 and 13.9 months, respectively. Progression of the disease was stabilised in a substantial number of women. Toxicity was mild, except for two cases of pulmonary embolism that might have been drug related (Burke et al. 2003). 

Clinical phase I and II data reveal bazedoxifene to be safe, very well tolerated, and efficacious. Phase III trials are currently in progress. 

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