Pharmacokinetic profile 1322 INDEX

Loteprednol (26) was selected for development based on various considerations including the therapeutic index, availability, synthesis, and "softness" (the rate and easiness of metabolic deactivation). Early studies in rabbits (106, 109) and rats (110) demonstrated that, consistent with its design, (26)isindeed active, is metabolized into its predicted metabolites (27, 28) (Fig. 15.10), and these metabolites are inactive (105). The pharmacokinetic profile of loteprednol indicated that, when absorbed systemically, it is rapidly transformed to the inactive metabolite (27) and eliminated from the body mainly through the bile and urine (110, 111, 113). It did not affect the intraocular pressure in rabbits (109), an observation confirmed later in various human studies (Fig. 15.12) (119). Consistent with the soft nature of this steroid, systemic levels or effects cannot be detected even after chronic ocular administration (120). 

The biodistribution of plasmid can be determined by measuring the rate of disappearance of radiolabeled DNA from the bloodstream and its accumulation in tissues or by the use of fluorescence microscopy to trace the leakage of dye-labeled plasmids from the vasculature. Pharmacokinetic analysis of in vivo disposition profiles of radiolabeled plasmid provides useful information on the overall distribution characteristics of systemically administered plasmids, with one critical limitation. The radiolabel represents both intact plasmid and its metabolites. The plasma half-life of plasmid is less than 10 min, and hence tissue distribution and pharmacokinetic parameters of plasmid calculated on the basis of total radioactivity are not valid at longer time points. Thus, polymerase chain reaction and Southern-blot analysis are required to establish the time at which the radiolabel is no longer an index of plasmid distribution. 

The decision of a national authority to allow a biowaiver based on the BCS should take into consideration the solubility and permeability characteristics as well as the therapeutic use and therapeutic index of the API, its pharmacokinetic properties, the similarity of the dissolution profiles of the multisource and the comparator products in standard buffers with a pH of 1.2, pH 4.5 and pH 6.8 at 37 °C. Data related to the excipients composition in the multisource product are also required. A systematic approach to the biowaiver decision has been established by the International Pharmaceutical Federation (FIP) and published in the Journal of Pharmaceutical Sciences (http //www3.interscience.wiley.com/cgi-bin/jhome/68503813). The relevant documents can also be downloaded from the FIP web site at http //www.fip.org/. These monographs provide detailed information which should be taken into account whenever available in the biowaiver consideration. 

If pharmacokinetics are dependent on dose or time, or a slow-release formulation is being studied, it is necessary to examine bioequivalence at steady state. For controlled-release formulations which are intended to produce relatively flat concentration-time profiles, an index of fluctuation is required, for example - Cn,jj])/C. A study at steady state may also be needed if the assay is not sensitive enough to quantify plasma concentrations of drug up to four half-lives after a single dose. Sometimes it is not technically feasible to assay a drug in plasma and it may then the justifiable to compare bioavailability by the total amount of drug excreted in urine, or pharmacodynamic data may be used, but these cases are exceptions. 

Narrow therapeutic index combined with the inter-individual variations in drug pharmacokinetics, response, and toxicity adds uncertainty to the clinical trials and use of novel anticancer agents. Pharmacogenetic and metabolomic profiling of the patients promise to at least partly address these concerns, thus helping in the individualization of medication for patients and improved... 

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