Bioequivalence (BE) l Assessment of bioequivalence l Pharmacokinetic endpoint studies

                                                 

For Generic medicines submission of an ANDA in the US, or a generic MAA in Europe is required to obtain the marketing approval. Generic medicine applications do not need to contain the pre-clinical and clinical studies required for originator medicines, with relatively simple bioequivalence studies being acceptable in their place.

Bioequivalence (BE): The absence of a significant difference in the rate and extent to which the active ingre­dient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

Assessment of bioequivalence

The assessment of BE of different drug products is based on the fundamental assumption that two products are equivalent when the rate and extent of absorption of the test/generic drug does not show a significant difference from the rate and extent of absorption of the reference/brand drug under similar experimental conditions as defined. As per the different regu­latory authorities, BE studies are generally classified as:

1.      Pharmacokinetic endpoint studies.

2.      Pharmacodynamic endpoint studies.

3.      Clinical endpoint studies.

       4.    In vitro endpoint studies.

 

In-general descending order of preference of these studies includes pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.

Pharmacokinetic: Pharmacokinetics, derived from the Greek words pharmakon (drug) and kinetikos (movement), is used to describe the absorption, distribution, metabolism, and excretion of a compound.

1.     Pharmacokinetic endpoint studies

These studies are most widely preferred to assess BE for drug products, where drug level can be determined in an easily accessible biological fluid (such as plasma, blood, urine) and drug level is correlated with the clinical effect. The statutory definition of BA and BE, expressed in rate and extent of absorption of the active moiety or ingredient to the site of action, emphasizes the use of pharmacokinetic measures to indicate release of the drug substance from the drug product with absorption into the systemic circulation.

Regulatory guidance recommends that measures of systemic exposure be used to reflect clinically important differences between test and reference products in BA and BE studies. These measures include

i)               area under the plasma concentration time curve / total exposure (_AUC0–t ^or _AUC0–∞ for single-dose studies and _AUC0–t for steady-state studies),

ii)              peak plasma concentration / peak exposure _(Cmax), and

iii)            early exposure (partial AUC to peak time of the reference product for an immediate- release drug product).

Reliance on systemic exposure measures will reflect comparable rate and extent of absorption, which, in turn, will achieve the underlying goal of assuring comparable therapeutic effects. Single dose studies to document BE were preferred because they are generally more sensitive in assessing in vivo release of the drug substance from the drug product when compared to multiple dose studies.

The following are the circumstances that demand multiple -dose study/steady state pharmacokinetics:

i.               Dose- or time-dependent pharmacokinetics.

ii.              For modified-release products for which the fluctuation in plasma concentration over a dosage interval at steady state needs to be assessed.

iii.            If problems of sensitivity preclude sufficiently precise plasma concentration measurements after single-dose administration.

iv.             If the intra-individual variability in the plasma concentration or disposition precludes the possibility of demonstrating BE in a reasonably sized single-dose study and this variability is reduced at steady state.

v.              When a single-dose study cannot be conducted in healthy volunteers due to tolerability reasons, and a single-dose study is not feasible in patients.

vi.             If the medicine has a long terminal elimination half-life, and blood concentrations after a single dose cannot be followed for a sufficient time.

vii.           For those medicines that induce their own metabolism or show large intra-individual variability.

viii.          For combination products for which the ratio of plasma concentration of the individual substances is important.

ix.             If the medicine is likely to accumulate in the body.

x.              For enteric coated preparations in which the coating is innovative.

 

Under normal circumstances, blood should be the biological fluid sampled to measure drug concentrations. Most drugs may be measured in serum or plasma; how­ever, in some drugs, whole blood (eg, tacrolimus) may be more appropriate for analysis. If the blood concentrations are too minute to be detected and a substantial amount (.40%) of the drug is eliminated unchanged in the urine, the urine may serve as the biological fluid to be sampled (eg, alendronic acid).

 Definition:

Modified-release products: Modified release products include extended release (controlled release or sustained release) products and delayed release products.

1.     Extended Release Products An extended release drug product is a dosage form that allows a reduction in dosing frequency and reduces fluctuations in plasma concentrations when compared to an immediate release dosage form. Extended release products can be formulated as capsules, tablets, granules, pellets, or suspensions. If any part of a drug product includes an extended release component, the product should be treated as a modified release dosage form for the purposes of establishing BE.

Delayed Release Products:  A delayed release drug product is a dosage form that releases a drug at a time later than immediately after administration (e.g., the drug product exhibits a lag time in quantifiable plasma concentrations). Typically, the coatings (e.g., enteric coatings) have been designed to delay the release of medication until the dosage form has passed through the acidic medium of the stomach. In vivo tests for delayed release drug products are similar to those for extended release drug products. We recommend that in vitro dissolution tests for these products document that they are stable under acidic conditions and that they release the drug only in a neutral medium (e.g., pH 6.8).