Bioavailability and Bioequivalence

Oral Formulations and Drug Properties

• Innovator drug formulations include the active drug and excipients.
• The properties of a drug are engineered into its formulation through the active moieties, excipients, and manufacturing process.
• For generic drugs, disintegration and dissolution profiles should be very similar to the innovator drug to ensure a similar effect-time relationship.

Key Terms

• Biopharmaceuticals considers the interactions between formulation adjuvants and drug release.
• Bioavailability is the rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action.
• Bioequivalence assesses whether generic and innovator formulations show no significant differences in the rate and extent to which the active ingredient is available at the site of action.
• Blood concentration-time profiles are a useful tool to assess bioavailability and bioequivalence.

Assessing Bioavailability

• Bioavailability data provides an estimate of the fraction of an orally administered dose that is absorbed.
• Absolute bioavailability is determined by comparing the AUC after oral administration to the AUC after an IV bolus injection, assuming IV injection results in 100% bioavailability.
• Relative bioavailability compares different formulations of the same drug.
• Equation for Absolute Bioavailability: F= (AUC oral * Dose IV) / (AUC IV * Dose Oral)
• Cmax over AUC can adjust for differing doses and indicate differences in absorption rates; a slower absorption rate leads to a smaller Cmax/AUC and longer Tmax

Innovator vs. Generic Drug Development

• Innovator drugs require extensive safety and efficacy trials (Phase 1-4) and about 20 years of patent protection.
• Generic drugs must show similarity to the innovator through bioequivalence studies and can be sold after patents expire, using an abbreviated process.

Bioequivalence Studies

• Bioequivalence is defined as the absence of significant differences in the rate and extent to which the active ingredient becomes available at the site of action when administered at the same molar dose under similar conditions.
• To test a generic, pharmaceutical equivalence must be shown first
• Pharmaceutical equivalence: same active ingredient, dosage form, route of administration, and strength/concentration as the innovator drug, but may vary in shape, scoring, release mechanism, packaging, excipients, color, flavors, and preservatives.

When to Perform Bioequivalence Studies

• To show that a generic drug has bioequivalence to the innovator drug.
• For innovator drugs to show bioequivalence between different batches or manufacturing locations.
• For innovator drugs, when making post-approval changes, such as a change in propellants.

Types of Bioequivalence Studies

• For oral dosage forms, pharmacokinetic studies are done, and decisions are made based on AUC, Cmax, and tmax.
• Bioequivalence can be assessed via urine pharmacokinetics for some drugs, or via pharmacodynamic studies for drugs that act topically or are inhaled.
• Standard bioequivalence studies are done for drugs with systemic action, comparing the pharmacokinetics of a test and reference product having the same active ingredient, strength, dosage form, and administration route.

Bioequivalence Study Designs

• Randomized Two-Period, Two-Sequence Crossover: Subjects randomly divided into two groups. One group receives test formulation first, then reference, the other does the reverse, with a washout period in between. This is the most efficient design but requires stable disease characteristics.
• Parallel Group: Subjects divided into two groups, one receiving only test formulation, the other reference formulation. This is shorter with no carryover effect, but has higher variability and needs a larger sample size for drugs with long half-lives
• Replicate Design: Subjects receive both test and reference formulations twice in four periods. This allows intra-subject variability assessment and may make it easier to meet bioequivalence statistics for highly variable drugs.

Study Design Details

• A washout period is important to ensure no drug carryover.
• Parallel designs are used for long half-life drugs.
• Replicate designs are used for highly variable drugs.

Subject Selection and Study Conditions

• Healthy adult volunteers, 18-45 years old are chosen to represent the general population with normal body weight.
• Pregnancy tests for women before the first and last dose.
• Elderly subjects (over 65) should be included if the drug is for the elderly population.
• Teratogenic drugs should only be studied in male volunteers; highly toxic drugs are tested in patients.

Study Procedures

• Bioequivalence studies should be done at the highest tablet strength; in vitro studies can support lower strengths.
• The study protocol needs IRB approval and must follow GCP standards.
• Typical PK studies have 24-36 volunteers.
• No coffee or alcohol within 24 hours of the study is permitted.
• Fasting conditions for overnight and for the first four hours of the PK study are required.
• The washout period should be about five half-lives.
• Subjects should use about 240 ml (8 oz) of water to swallow the drug.
• 12-18 samples are collected in a single-dose study, with 3-4 at the terminal phase.
• Drug concentration should be followed for at least three terminal half-lives. The FDA allows stopping at 72 hours for long half-life drugs.
• There should be standardized meals and exercise.
• Validated analytical methods for drug concentration measurement are required.
• Primary PK parameters are AUC and Cmax, with Tmax as a secondary parameter.
• Some should be done in a fed state for drugs taken with food or for modified-release formulations, which require high-calorie food studies due to the risk of "food dumping".

Multiple Dose Studies

• Multiple dose studies are necessary for higher drug concentrations, to study drug accumulation, or for toxic drugs.
• They are also needed for some modified release formulations, combination products, drugs that induce their own metabolism, or those with nonlinear pharmacokinetics.

Statistical Evaluation

• A 20-25% difference in active drug concentration in blood is considered clinically insignificant.
• Bioequivalence is established if the AUC and Cmax estimates of the generic are between 80% and 125% of the innovator values.
• An ANOVA test is used for Cmax and AUC; tmax is a secondary parameter.
• 90% confidence intervals (CI) for the geometric mean ratios of Cmax and AUC must be within the 80-125% range (0.8 to 1.25).
• Tmax is assessed non-parametrically, with the 90% CI within a clinically acceptable range.

Example of Bioequivalence Determination

• The reference product tested against itself will have a mean ratio of 1.0, with confidence intervals contained within 0.8 and 1.25.
• A non-equivalent product may have a mean within 0.8 and 1.25 but the confidence intervals may fall outside of that range.
• An equivalent product will have both a mean and confidence intervals within the range of 0.8 and 1.25.

Tighter Limits for Some Drugs

• For drugs with a narrow therapeutic index, serious dose-related toxicity, steep dose-response curves, or nonlinear pharmacokinetics, the limits may be tighter.

Summary of Key Points

• Single-Dose Studies: more sensitive, shorter duration, usually done at the highest strength, measure racemic mixtures.
• Multiple-Dose Studies: less sensitive, longer duration, may be needed for all strengths if high variability

Biowaivers and the Biopharmaceutical Classification System (BCS)

• Biowaivers are situations where pharmacokinetic studies are not required, and in vitro studies are sufficient, such as for drug solutions.
• The BCS classifies drugs based on their solubility and permeability.

BCS Classes

• Class I: High permeability and solubility, minimal formulation effects.
• Class II: High permeability, low solubility, significant formulation effects on dissolution.
• Class III: Low permeability, high solubility, absorption affected by permeability.
• Class IV: Low permeability and solubility, formulation changes affect bioequivalence.
• Biowaivers can be granted for Class I drugs with rapid dissolution, where in vitro data on permeability, solubility, and dissolution are sufficient.

Conclusion

• Bioavailability is the rate and extent to which an active ingredient is absorbed.
• Bioequivalence is confirmed when the 90% confidence intervals for the ratios of AUC and Cmax of the test product fall between 0.8 and 1.25 after log transformation, relative to the reference product.
• Drug products meeting bioequivalence are considered therapeutically equivalent.
• In vivo studies can be waived for lower strengths if in vitro characteristics are similar to the higher strength.
• Class I drugs may be eligible for biowaivers.

Understand bioavailability studies, bioequivalence of generic drugs, and the factors affecting drug absorption. Explore the role of excipients, particle size, and in vivo performance. Learn why blood profiles matter and considerations for generic tablet formulation.