Bioavailability studies

Eventually, the proposed method was successfully applied to quantify clarithromycin in spiked human plasma and real samples from healthy volunteers after oral administration of the dmg indicating the utility of this method for clinical and bioavailability studies. 

Bioavailability studies play a critical role in the evaluation of product formulations throughout the entire development process. 

Exposures of Children. Children will be exposed to americium in the same manner as adults in the general population (i. e., ingestion of food and water and inhalation of air). Americium is potentially found at hazardous waste sites at elevated levels. Since children may have oral exposure to soil through hand-to-mouth activity, bioavailability studies of americium in soil via the oral route may be useful to assess the risk of this type of exposure. 

For most practical purposes, a first-order process may be deemed complete if it is 95% or more complete. Table 1 shows that five half-lives must elapse to reach this point. Thus the elimination of a drug from the body may be considered to be complete after five half-lives have elapsed (i.e., 97% completion). This principle becomes important, for example, in crossover bioavailability studies in which the subjects must be rested for sufficient time between each drug administration to ensure that washout is complete. 

Bioavailability studies are frequently carried out for the sole purpose of comparing one drug product... 

All piroxicam batches were manufactured in compliance with Good Manufacturing Practices, and three formulations having fast, moderate, and slow dissolution were chosen for comparison to a lot of the innovator s product in a human bioavailability study [100]. The resulting pharmacokinetic data provided still another opportunity to examine the effects of formulation variables. To explore the relationship between the in vitro dissolution of piroxicam from these capsules and in vivo absorption, Polli [ 102] used the following previously described [145] deconvolution-based model ... 

The ability of NB-355 to stimulate locomotor activity and induce dyskinesia in MPTP-treated squirrel monkeys was studied (MPTP induces parkinsonism) [9], NB-355 was similar to L-dopa in stimulating locomotor activity. Furthermore, NB-355 induced less severe dyskinesia than was seen with L-dopa. Some other prodrugs of L-dopa include short-chain alkyl esters (methyl, ethyl, isopropyl, butyl, hydroxypropyl, and hydroxybutyl) intended for rectal absorption [10], These esters of L-dopa have high water solubility (>600 mg/mL). Initial bioavailability studies indicated that all of these esters, with the exception of the hydroxypropyl ester, resulted in significantly greater bioavailability than that obtained with L-dopa itself. However, given the high level of esterase activity in the small intestine, the use of these compounds is limited to rectal administration. 

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. 

Bioavailability studies need to be performed to evaluate the differences between conventional and organic crops, e.g. human intervention studies. 

Bioavailability and bioequivalence are also usually assessed in animals. Such studies are undertaken as part of pharmacokinetic and/or pharmacodynamic studies. Bioavailability relates to the proportion of a drug that actually reaches its site of action after administration. As most biopharmaceuticals are delivered parenterally (e.g. by injection), their bioavailability is virtually 100 per cent. On the other hand, administration of biopharmaceuticals by mouth would, in most instances, yield a bioavailability at or near 0 per cent. Bioavailability studies would be rendered more complex if, for example, a therapeutic peptide was being administered intranasally. 

Bone is very sensitive to dietary factors such as the amount of calcium present in the diet and the availability of that calcium when all other nutrients are present in adequate amounts (46, 47). This is especially true of the growing animal which is utilized in most bioavailability studies. Adult animals, however, may also be used. Krook et al (48) caused osteoporosis in adult dogs in 42 weeks by feeding a low-calcium high-phosphorus diet. The bones were radiologically normal after 28 weeks of calcium repletion (48). The ash contents of the vertebral bones of these dogs were much more responsive to dietary calcium and phosphorus manipulation than were the humeri and femora (48). 

The Time for Maximum Concentration, 7max, is the third important component of bioavailability studies. It is a measure of the rate of drug absorption. A lower 7max represents a faster absorption and a higher Tmax represents a slower absorption. Similar to Cmax, the 7max is read directly from the plasma concentration versus time profile. The 7max in Figure 12.2 is 6 hours. 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

Kalantzi L, Ftirst T, Abrahamsson B, Goumas K, Kalioras V, Dressman J, Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability studies in the fasting and fed states. Proceedings of the AAPS Annual Meeting, Salt Lake City, UT, 2003. 

Figure 28.1 Requirements for a biowaiver of bioequivalence and bioavailability studies.

Absolute bioavailability studies In vivo intestinal perfusion... 

Li, X., Wang, G., Sun, J., Hao, H., Xiong, Y., Yan, B., Zheng, Y., and Sheng, L. (2007b). Pharmacokinetic and absolute bioavailability study of total panax notoginsenoside, a typical multiple constituent traditional Chinese medicine (TCM) in rats. Biol. Pharm. Bull. 30, 847-851. 

Has a bioequivalence that has been demonstrated by appropriate bioavailability studies... 

The determination of these compounds in biological fluids is crucial for several reasons such as investigating overdosing (toxicological monitoring), conducting pharmacokinetic and bioavailability studies, and measuring compliance. 

Has it been necessary to repeat stability or bioavailability studies because of differences in standards for excipients ... 

D. Comparative bioavailability study (water-soluble micelles vs a regular supplement)... 

In summary, our bioavailability study provided for fhe firsf time data for fhe shorf-ferm bioavailability of ot-tocopherol solubilizate in comparison to regular fat-soluble preparations. Our results pointed to a higher short-term bioavailability of vitamin E in micelles versus fat-soluble forms of fhis vifamin in healthy adult volunteers both with regard to AUCs and with regard to maximum increases in plasma vitamin concentrations. 

Most of fhe above-mentioned bioavailability, intervention, and case studies came to the conclusion that water-miscible or water-soluble preparations of faf-soluble vitamins were superior to regular supplements. Based on the evidence from our own bioavailability study as well as from fhe studies mentioned above, it therefore seems justified to assume that fat-soluble vitamin deficit patients with fat maldigestion and/or malabsorption can be corrected more efficiently by using water-soluble as opposed to fat-soluble preparations. Another advantage of water-soluble preparations in general might be that lower daily doses are required when compared to fat-soluble preparations to achieve the same results. 

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