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PubMed2000

Overview status of preclinical safety assessment for immunomodulatory biopharmaceuticals.

Scientists from academia, industry, FDA, European and Japanese regulatory groups met to discuss key considerations that are central to the safe and expeditious development of novel biologic agents that are thought to act by modulation of the host immune system. In the presentations and case studies, particular attention was given to the current clinical experience with immunosuppressant agents. Many new biologic agents (such as humanized monoclonal antibodies) have been developed to interact in a highly specific manner with their target. However, their pharmacologic properties may be more complex than originally appreciated, impacting on clinical trial designs. The goal of preclinical safety assessment should be to provide some assurance that patients will be protected from any unacceptable risks by defining "safe" and "active" doses. For immunomodulatory molecules, particular attention is paid to defining potential for increased risks of lymphoproliferative disorders, opportunistic infections, and immune impairment. To address these issues, a wide variety of preclinical studies, mainly in non-human primates, have been performed for the purpose of assessing the potential risk of drug-induced, human immunotoxicity. Case studies presented at this symposium showed the feasibility of assessing humoral and cell-mediated aspects of the immune system, using antigen and neoantigen challenges, immunohistochemical, and flow cytometric (FACS) methods. In some cases, homologous forms of the biologic agent and "humanized" transgenic models have been used to assess potential clinical risks. These data have been useful in providing some assurance that severe adverse effects would not be induced in patients. Despite these limitations, it is important that industry sponsors provide information to regulatory authorities, the clinical investigator, and patients that provides the best feasible basis for risk assessment, safe clinical trial design, informed consent, and eventually, appropriate labeling. It is recognized that existing preclinical models often have significant limitations. Consequently, the sponsor's and regulatory authority's experienced judgement has determined whether or not the purported benefits of the novel therapeutic agent are balanced by the potential short- and long-term risks. In this field of development, preclinical models often need to reflect recent technology innovations; therefore, these models are not always "validated" in a conventional sense. Experience to date suggests that improved methods and approaches are needed as these agents are developed for use in lower or moderate risk patient populations. Consequently, there is an increased need for an industry/regulatory partnership in order to achieve progress in these risk assessment areas.

Adjuvants, Immunologic↗
PubMed1981

Biopharmaceutical studies on hydantoin derivatives. I. Physico-chemical properties of hydantoin derivatives and their intestinal absorption.

The physico-chemical properties of a series of hydantoin derivatives and their intestinal absorption from solution were studied. The introduction of the benzenesulfonyl group at the 1-position of the hydantoin ring greatly affects the physico-chemical properties: the acid dissociation constants were increased 1000-fold and the partition coefficients were increased 100- to 1000-fold in the chloroform/water system and 10- to 100-fold in the n-octanol/water system. The solubilities of 1-benzenesulfonylhydantoin derivatives increased with increasing pH of the solution at pH more than 5, but the solubilities of the 1- unsubstituted hydantoin derivatives were scarcely dependent on the pH of the solution in the pH 1 to 8 region. The intestinal absorption from solution was found to be caused by the passive transport according to the first-order kinetics. The rate constants of absorption of 1-benzenesulfonylhydantoin derivatives were rather large even under the condition where they were 99% ionized in the solution than that of the corresponding 1-unsubstituted hydantoin derivatives which exist mainly as the unionized from under the same condition. The intestinal absorption from a solution and the partitioning to chloroform produced linear free energy relationships to each other for the 1-benzenesulfonylhydatoin derivatives and for the 1-unsubstituted hydantoin derivatives independently. However when the partition coefficients in the n-octanol/water system were applied, the hydroxyl derivatives were found to deviate from linear relationships. On the basis of the results, a suggestion was made on the in vivo behavior and the bioavailability.

Animals↗
PubMed1989

Biopharmaceutical evaluation of sustained-release ethylcellulose microcapsules containing amoxicillin using beagle dogs.

A beta-lactam antibiotic, amoxicillin, was microencapsulated with ethylcellulose using a solvent evaporation process in liquid paraffin containing sorbitan tristearate as a dispersing agent, and the microcapsules obtained showed first-order drug release. Usage of the previous log-log relationship of cefadroxil between in vitro dissolution half-lives (T50) and the experimental release rate constants (k'r) of the drug in vivo, and the nomogram for the design of satisfactory sustained-release preparations resulted in the prediction that ethylcellulose microcapsules containing 60% amoxicillin would show the most effective sustained-release pattern. Prepared microcapsules containing various amounts of amoxicillin were administered to beagle dogs and it was found that above prediction was correct. In addition, a more precise log-log correlation concerning amoxicillin was also undertaken, good linearity was observed and the decline was very similar to that of cefadroxil.

Amoxicillin↗