Pharmacokinetic studies INDEX

The applicant should provide justification for using the racemate. Where the interconversion of the enantiomers in vivo is more rapid than the distribution and elimination rates, then use of the racemate is justified. In cases where there is no such interconversion or it is slow, then differential pharmacological effects and fate of the enantiomers may be apparent. Use of the racemate may also be justified if any toxicity is associated with the pharmacological action and the therapeutic index is the same for both isomers. For preclinical assessment, pharmacodynamic, pharmacokinetic (using enantiospecific analytical methods) and appropriate toxicological studies of the individual enantiomers and the racemate will be needed. Clinical studies on human pharmacodynamics and tolerance, human pharmacokinetics and pharma-cotherapeutics will be required for the racemate and for the enantiomers as appropriate. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

In general, bioequivalence is demonstrated if the mean difference between two products is within 20% at the 95% confidence level. This is a statistical requirement, which may require a large number of samples (e.g. volunteers), if the drug exhibits variable absorption and disposition pharmacokinetics. For drugs for which there is a small therapeutic window or low therapeutic index, the 20% limit may be reduced. The preferred test method is an in vivo crossover study and, since this occurs in the development phase, necessitates the emplo)unent of volim-teers. These studies are, therefore, expensive and animal experiments may be substituted, or in vitro experiments if they have been correlated with in vivo studies. 

For styrene, the default intraspecies UF of 10 was reduced to 3 in the calculation of the RfC value, because the lower 95% limit of the exposure extrapolation for a NOAEL in a human cross-sectional study was used and the biologic exposure index had been shown to account for variation in pharmacokinetic and physiologic measures, such as the alveolar ventilation rate (EPA 1993). 

CDER, CBER. Pharmacokinetics in patients with impaired renal hmction — study design, data analysis, and impact on dosing and labeling. Guidance for Industry, Rockville FDA 1998. (Internet at http //www.fda.gov/cder/guidance/index.htm.)... 

The effects of oral itraconazole (400 mg on the first day then 200 mg/day for 3 days) on the pharmacokinetics of a single oral dose of prednisolone 60 mg or methylprednisolone 48 mg have been studied in 14 healthy men in a two-period, crossover study (97). Plasma cortisol concentrations were determined as a pharmacodjmamic index. The disposition of prednisolone was unchanged. 

In the third stage, i.e., the various phases of clinical trials, pharmacokinetics is studied in detail in order to obtain the therapeutic index, to study drag-drag interactions, and to design dosage regimes. 

United States Food and Drug Administration. 1998. Guidance for Industry Pharmacokinetics in Patients With Impaired Renal Function Study Design, Data Analysis and Impact on Dosing and Labeling. US Dept Flealth and Fluman Services Washington accessed March 16, 2005, from http //www.fda.gov/cder/guidance/index.htm. 

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. 

Recording details of the studies, including the models used and associated parameter values reported, is an obvious starting place. Additional details include the chemical analysis method, the pharmacokinetic analysis method, the studied population (specifically subpopulations), number of healthy volunteers or patients, number of pharmacokinetic samples per patient, the dose, the formulation, and the route of administration. If one publication includes several groups of patients (or the same patient received two different formulations/concomitant medications), then each cohort may need to be treated as a repeated measure of the same study or within the same study, which may be indexed according to a study or patient covariate. 

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). 

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