Bioequivalency single-dose

Pharmacokinetics One emtricitabine/tenofovir disoproxil fumarate tablet was bioequivalent to 1 emthcitabine capsule (200 mg) plus 1 tenofovir disoproxil fumarate tablet (300 mg) following single-dose administration to fasting healthy subjects. 

For bioequivalence studies, the two formulations of same drug is administered orally as single dose. Figure 1.4.2 shows that in the study the different parameters are obtained. Firstly the peak height which represents the highest concentration of the drug reached in the blood at a particular time i.e. time of peak concentration. The area... 

Narrow therapeutic range drugs Single-dose bioequivalence study. This study may be waived if in vitro/in vivo correlation is established. Changes in release controlling excipients in formulation should be within the range of release controlling excipients in the established correlation. 

Table8.4 Formulation characteristics of test and reference LMWH (tinzaparin) formulations evaluated in a single-dose crossover (bioequivalence) design.

Table 8.6 Pharmacokinetic and bioequivalence metrics from a single-dose, two-way crossover study of LMWH (tinzaparin) formulations administered to healthy volunteers.

In general, oral dose forms are usually considered to be bioequivalent when confidence intervals for the ratios of their geometric mean C and area-under-the-curve (AUC from time zero to infinity for single doses or within a dosing interval at steady state) are within the range 0.8-1.25 and any difference between their Tma s is within clinically acceptable limits. This range may be tightened for medicines that have ... 

Levy (1964), Jusko (1971) and Smolen (1971, 1976) described the analysis of dose-response time data. They developed a theoretical basis for the performance of this analysis from the data obtained from the observation of the time course of pharmacological response, after a single dose of drug, by any route of administration. Smolen (1976) extended the analysis to application of dose-response time data for bioequivalence testing. 

The design of the study should minimize the variability that is not caused by formulation effects and eliminate bias as far as possible. Test conditions should reduce variability within and between subjects. In general, for a pharmacokinetic bioequivalence study involving a multisource and a comparator product, a two-period, single-dose, cross-over study in healthy volunteers will suffice. However, in certain circumstances, an alternative, well-established and statistically appropriate study design may be adopted. 

A single-dose cross-over pharmacokinetic bioequivalence study of an orally administered product with a long elimination half-life can be conducted provided an adequate wash-out period is used between admnistrations of the treatments. The interval between study days should be long enough to permit elimination of essentially all of the previous dose from the body. Ideally, the interval should not be less than five terminal elimination half-lives of the active compound or metabolite, if the latter is measured. Normally the interval between study days should not exceed 3-4 weeks. If the crossover study is problematic, a pharmacokinetic bioequivalence study with a parallel design may be more appropriate. 

Although the two-period crossover design has certain intrinsic weaknesses, intra-individual variation is usually smaller than variation between subjects, and bioequivalence can usually be established using a smaller number of subjects in a crossover study. The order in which subjects receive single doses of the different formulations must be randomised and an adequate interval allowed between doses to ensure washout. The number of subjects will depend on the variability of the kinetics of the compound. A power calculation should be performed using historical data, if possible. In practice, the minimum number of volunteers needed is 12 and the maximum usually about 24 but is occasionally more. The number and times of blood samples is a critical a sufficient number of samples is required around the to permit and to be identified with adequate accuracy. Sampling should continue for at least 3-4 half-lives and later samples should be spaced so that no more than about 15% (or ideally 10%) of the AUC has to be determined by extrapolation or interpolation between points. Model-fitted data are usually not acceptable should be obtained directly from the observed concentration data and... 

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. 

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