Pharmacokinetics bioequivalence

For certain medicines and dosage forms, in vivo documentation of equivalence, through either a pharmacokinetic bioequivalence study, a comparative pharmacodynamic study or a comparative clinical trial, is regarded as especially important. In vivo documentation of equivalence is needed when there is a risk that possible differences in bioavailability may result in therapeutic inequivalence (2). Examples are listed below. 

Bioequivalence studies are designed to compare the in vivo performance of a multisource product with that of a comparator product. Pharmacokinetic bioequivalence studies on products designed to deliver the API for systemic exposure serve two purposes ... 

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. 

The comparator product in this study should be a pharmaceutically equivalent modified-release product. The pharmacokinetic bioequivalence criteria for modified-release products are basically the same as for conventional-release dosage forms. 

The number of subjects required for a sound pharmacokinetic bioequivalence study is determined by ... 

Pharmacokinetic bioequivalence studies should generally be performed with healthy volunteers. Clear criteria for inclusion and exclusion should be stated in the study protocol. If the pharmaceutical product is intended for use in both sexes, the sponsor may wish to include both males and females in the study. The risk to women will need to be considered on an individual basis, and if necessary, they should be warned of any possible dangers to the fetus if they should become pregnant. The investigators should ensure that female volunteers are not pregnant or likely to become pregnant during the study. Confirmation should be obtained by urine tests just before administration of the first and last doses of the product under study. 

Generally, evaluation of pharmacokinetic bioequivalence will be based upon the measured concentrations of the parent drug released from the dosage form rather than the metabolite. The concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution and elimination. It is important to state a priori in the study protocol which chemical entities (pro-drug, drug (API) or metabolite) will be analysed in the samples. 

A non-stereoselective assay is currently acceptable for most pharmacokinetic bioequivalence studies. When the enantiomers have very different pharmacological or metabolic profiles, assays that distinguish between the enantiomers of a chiral API may be appropriate. Stereoselective assay is also preferred when systemic availability of different enantiomers is demonstrated to be non-linear. 

The statistical method for testing pharmacokinetic bioequivalence is based upon the determination of the 90% confidence interval around the ratio... 

If the pharmacokinetic bioequivalence of fixed-dose combination (FDC) products is assessed by in vivo studies the study design should follow the same general principles as described in previous sections. The multisource FDC product should be compared with the pharmaceutically equivalent comparator FDC product. In certain cases (e.g. when no comparator FDC product is available on the market) separate products administered in free combination can be used as a comparator (5). Sampling times should be chosen to enable the pharmacokinetic parameters of all APIs to be adequately assessed. The bioanalytical method should be validated on respect... 

If a clinical bioequivalence study is considered as being undertaken to prove equivalence, the same statistical principles apply as for the pharmacokinetic bioequivalence studies. The number of patients to be included in the study will depend on the variability of the target parameters and the acceptance range, and is usually much higher than the number of subjects needed in pharmacokinetic bioequivalence studies. 

The methodology for establishing equivalence between pharmaceutical products by means of a clinical trial in patients with a therapeutic end-point has not yet evolved as extensively as for pharmacokinetic bioequivalence trials. However, some important items which need to be defined in the protocol can be identified. 

On the basis of solubility and permeability of the API, and dissolution characteristics of the dosage form, the BCS approach provides an opportunity to waive in vivo pharmacokinetic bioequivalence testing for certain categories of immediate-release drug products (28). Oral drug products not eligible for a so-called biowaiver based on the BCS approach are described under section 5.1 (a). 

Market approval of generic medicines requires pharmacokinetic bioequivalence studies. In bio-equivalence studies, the product to be investigated is compared to an innovator product. Products are regarded as bio-equivalent if the 90 % confidence interval of the AUC-ratio and Cmax are within 80-125 % of the reference product. If the confidence interval is within these limits, this means that the average will deviate far less from the corresponding value found for the innovator product. 

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