AUC 外推至无穷

The total AUC ( AUC0-∞ ) represent the complete drug exposure, extending from time 0 to infinity. It is calculated as:

We previously described how to calculate AUC0-t, which accounts for drug exposure up to the last measurable concentration. To determine AUCt₋∞, we must extrapolate beyond this point using the terminal elimination phase of the drug.

Extrapolating AUC to infinity relies on several key assumptions:

1. Mono-exponential decline: After the last measurable concentration, the drug follows a mono-exponential decay, meaning its concentration decreases at a constant rate.
2. Accurate elimination rate constant (λz): The terminal elimination rate constant, λz, is correctly estimated from the observed data and remains consistent over time.
3. Elimination as the only process: No other processes, such as continued absorption or redistribution, significantly influence the drug’s concentration during the terminal phase.

In most cases, these assumptions hold true. At low concentrations, drug elimination typically follows a mono-exponential pattern, and λz remains stable. Additionally, absorption and distribution phases are usually complete by the time the terminal phase is observed, ensuring that elimination is the dominant process governing drug disposition. However, it is important to understand how the extrapolation is done and when it might not be applicable.

If these assumptions hold, we can treat the extrapolated portion of the AUC similarly to an IV bolus dose. When a drug is administered as an IV bolus and follows mono-exponential decline, its AUC can be calculated as:

Applying the same principle, we can estimate the extrapolated AUC using the last measurable concentration (Clast) and the elimination rate constant (kel):

This extrapolated AUC is then added to the observed AUC0-t to determine AUC0-∞, the total drug exposure.

Additionally, a useful metric is the percentage of AUC contributed by extrapolation, which helps assess the reliability of AUC0-∞ . It is calculated as:

A high percentage of extrapolated AUC may indicate uncertainty in estimating total drug exposure, particularly if Clast is close to the assay’s limit of quantification or if λz is poorly defined.

If the % extrapolated AUC exceeds 20-30%, the total AUC (AUC0-∞) may be considered unreliable. This does not indicate a calculation error but rather a limitation in the available data. A high extrapolated percentage suggests that the terminal phase is not well-characterized, meaning the elimination rate constant (λz) may be inaccurately estimated.

To improve the reliability of total AUC calculations, additional sampling in the terminal phase is recommended. More data points beyond Clast will provide a more accurate estimate of λz, leading to a more precise determination of both AUC0-t and AUC0-∞.

If Clast is near the limit of quantitation of the assay, consider trying a lower limit of quantification (LLOQ) if method sensitivity allows. If quantifiable concentrations cannot be reliably obtained, caution should be exercised when interpreting AUC0-∞, and alternative approaches, such as truncated AUC, may be considered.

In Phoenix WinNonlin’s NCA object, users can apply the rule to flag cases where the extrapolated AUC exceeds a user-defined percentage of the total AUC. If this threshold is exceeded, AUC0-∞ is flagged as not meeting the criteria. Users can then choose to exclude this parameter from summary statistics, ensuring that only reliable values are reported.

Screenshot from Phoenix 8.5