How is bioequivalence (Bioequivalence) study data used to determine if a generic drug is equivalent to a brand-name drug, such as linagliptin (Linagliptin), in terms of pharmacokinetic parameters like area under the curve (AUC) and maximum concentration (Cmax)?

From the Guidelines

Bioequivalence studies are used to determine if a generic drug like linagliptin is therapeutically equivalent to its brand-name counterpart by comparing their pharmacokinetic parameters, such as area under the concentration-time curve (AUC) and maximum concentration (Cmax), to ensure therapeutic equivalence and safety. In these studies, healthy volunteers receive both the generic and brand-name versions in a crossover design, and blood samples are collected over time to measure drug concentrations. The key parameters compared are:

• The area under the concentration-time curve (AUC), which reflects total drug exposure
• Maximum concentration (Cmax), which indicates peak drug levels For a generic linagliptin to be considered bioequivalent, the 90% confidence intervals for the ratios of these parameters (generic/brand) must fall within 80-125% of the reference drug, as stated in the guidelines 1. This range accounts for acceptable biological and statistical variation while ensuring therapeutic equivalence. The time to reach maximum concentration (Tmax) is also evaluated but has more flexible criteria. These strict statistical comparisons ensure that generic linagliptin will produce the same clinical effect and safety profile as the brand-name version, allowing healthcare providers to confidently prescribe the generic alternative, as supported by the evidence 1. This process eliminates the need for generic manufacturers to repeat extensive clinical trials, making medications more affordable while maintaining efficacy and safety, which is a key consideration in real-life clinical practice 1.

From the FDA Drug Label

The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes mellitus. After oral administration of a single 5 mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L. Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4.

Bioequivalence study data is used to determine if a generic drug is equivalent to a brand-name drug, such as linagliptin, in terms of pharmacokinetic parameters like:

• Area under the curve (AUC)
• Maximum concentration (Cmax) The data from the drug label shows that linagliptin has a mean plasma AUC of 139 nmol*h/L and a Cmax of 8.9 nmol/L after a single 5 mg dose. To determine bioequivalence, the generic drug must have similar pharmacokinetic parameters to the brand-name drug, linagliptin, as defined by the FDA 2. The FDA considers a generic drug to be bioequivalent to a brand-name drug if the 90% confidence intervals for the ratio of the generic drug to the brand-name drug for AUC and Cmax fall within the range of 80% to 125% 2.

From the Research

Bioequivalence Study Data

Bioequivalence study data is used to determine if a generic drug is equivalent to a brand-name drug in terms of pharmacokinetic parameters like area under the curve (AUC) and maximum concentration (Cmax) 3, 4, 5, 6.

• The US Food and Drug Administration requires that the 90% confidence interval of the pharmacokinetic (PK) ratio should lie between 0.80 and 1.25 for a generic drug to be deemed bioequivalent to a branded drug 3.
• Bioequivalence is studied in randomized crossover trials that compare the generic drug with the reference agent, and the relevant outcome measures are pharmacokinetic (PK) parameters such as peak drug concentration and area under the curve 3.
• The ratio of each PK characteristic of the generic drug to the reference drug is computed, with an ideal value of 1:1, or just 1.00, indicating a perfect match, or perfect bioequivalence 3.

Pharmacokinetic Parameters

The pharmacokinetic parameters used to assess bioequivalence include:

• Area under the plasma concentration-time curve (AUC), which characterizes the extent of drug absorption 4, 5, 6.
• Maximum drug concentration (Cmax), which characterizes the absorption rate 4, 5, 6.
• Time of maximum plasma concentration (tmax) 5.

Example: Linagliptin

Linagliptin is an oral, highly selective inhibitor of dipeptidyl peptidase-4, used in the management of type 2 diabetes mellitus 7.

• The efficacy of oral linagliptin in the treatment of adults with type 2 diabetes has been investigated in several double-blind, multicentre trials 7.
• Linagliptin was more effective than voglibose in a 26-week monotherapy trial and noninferior to glimepiride when used as add-on therapy to metformin in a 104-week study 7.

Study Designs

Bioequivalence studies can be conducted using various designs, including:

• Crossover design, which is the most common design used in bioequivalence studies 3, 5, 6.
• Parallel design, which is rarely used in bioequivalence studies 6.
• Replicated design, which can be used to increase the precision of the estimates 5.
• Add-on design, which can be used to compare the bioavailability of two or more drug products 5.