Safety and Bioavailability

Safety and bioavailability of the herb in the form most likely to be used (i.e., powder, tea, tincture, concentrated extract, etc.)... 

A wide variety of packaging (cans, bottles, composite canisters, pouches) is currently used for infant formulas, and current regulations define methods to assure safety and bioavailability. If new ingredients require novel package forms, the safety assessment must account for this. 

The SOSA approach [33-37] uses old drugs for new pharmacological targets. The aim is to screen only a limited number of drug molecules that are structurally and therapeutically diverse and have known safety and bioavailability in humans. As a result, it is expected that such an approach might reduce the time and the cost compared to a standard hit identification process. The SOSA approach proceeds in two steps ... 

Assess the drug s safety and biological activity in the laboratory and animal studies Establish the safety and bioavailability of the compound in humans. This Is typically done in studies using healthy volunteers... 

The nasal tissue is highly vascularized and provides efficient systemic absorption. Compared with oral or subcutaneous administration, nasal administration enhances bioavailability and improves safety and efficacy. Chitosan enhances the absorption of proteins and peptide drugs across nasal and intestinal epithelia. Gogev et al. demonstrated that the soluble formulation of glycol chitosan has potential usefulness as an intranasal adjuvant for recombinant viral vector vaccines in cattle [276]. 

Development candidates must be measured against multiple performance criteria, including such aspects as potency, safety, and novelty. Conflict may be experienced between the criteria, in which improved performance in one criterion can only be achieved at the expense of detriment to another. In this situation—as is often the case for activity against bioavailability—a trade-off is said to exist between the objectives. A trade-off between potency and safety may also be present. 

To maximize safety and therapeutic efficacy, potential drugs are required to be highly specific for their protein target and orally bioavailable. In addition, for a drug candidate to reach the market, it must be patentably novel. A computational approach therefore needs to find novel compounds with well-defined pharmacological properties from the vast space of possible organic compounds ( chemical space ). 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Other possibilities for insoluble materials are to mix the desired amount of material with a small amount of the animal s diet or to use capsules. The difficulty with the diet approach is the likelihood that the animal will not consume all of the treated diet or that it may selectively not consume chunks of test material. Use of capsules, meanwhile, is labor intensive. In rare cases, if all of these approaches fail, it may not be possible to test a material by oral administration. In capsules, particle size is generally inversely related to solubility and bioavailability. However, milling of solids may adversely affect their chemical nature and/or pose issues of safety. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

Other offices within CDER may become involved in the review process via consults. For example, the Office of Epidemiology and Biostatistics analyzes statistical data, the Office of Research Resources provides bioavailability reviews, and the Office of Compliance determines from the results of inspections whether the firms meet FDA s Current Good Manufacturing Practice (cGMP) regulations. Advisory committees composed of independent experts are often asked to meet and further analyze the data. Often they also advise as to what additional data and information may be needed. After FDA s review is completed, FDA issues either a Summary Basis of Approval (SBA) for the dmg or a recommendation against approval. If approved, FDA releases the SBA and a summary of the safety and effectiveness data to the general public. 

However, the information derived from a detailed pharmacokinetic study will help to anticipate potential botanical product-drug interactions, to optimize the bioavailability, the quality, and hence the efficacy of herbal medicines, to support evidence for the synergistic nature of herbal medicines, and to better appreciate the safety and toxicity of the plant. Because pharmacokinetic studies with herbal medicines are often complicated by their chemical complexity and by the fact that the active compounds are often unknown, it could be one future issue to assess bioavailability by measuring surrogate parameters in plasma or tissue instead of directly assaying putative active compounds in the blood. In summary, to use HMPs in an evidence-based approach and to achieve the status rational phytomedicine, more experimental studies are needed to characterize the bioavailability and pharmacokinetics of botanical products. 

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