- Datapharm Australia
- May 19, 2023
Non-compartmental analysis (NCA) is a type of pharmacokinetics (PK) analysis and is the most commonly used approach for establishing initial exposure characteristics for a drug prior to its introduction to a clinic. This is generally more suited for single studies and Phase 1 or non-clinical (such as clinical pharmacology or toxicology) studies.
NCA is model independent and makes no assumptions about the body compartments. It almost exclusively relies upon algebraic equations, including extrapolations, and linear relationships are assumed between adjacent time points. The results of an NCA are summary statistics, which can be used to describe the drug’s PK profile. The main summary parameters are generally the area under the curve (AUC) and maximum concentration (Cmax), the two measures of bioequivalence.
AUC measures the exposure of drug experienced by the subject, representing drug bioavailability. It is usually measured by the trapezoidal method: calculating the individual areas between each adjacent observed concentration as if they formed a trapezoid. AUClast is the total AUC from time zero (drug administration) to the last evaluated time point, calculated by summing the areas of all the trapezoids to this time point.
AUC can be approximately extrapolated from time zero to infinity (AUC0-∞). However, this is only reliable under certain conditions, including if AUClast would compromise at least 80% of the calculated AUC0-∞. It also assumes that the drug concentration declines in a mono-exponential fashion, the rate of decline is accurately determined by the observed terminal elimination rate constant, and no other processes besides elimination are involved (these are usually valid assumptions). AUC0-∞ requires calculation of the elimination rate constant (Ke), which in NCA can be estimated using a minimum of three data points, occurring after Tmax.
When performing NCA, a number of samples should be taken per subject, with the time windows specified in the study protocol. The reasons for taking multiple samples include:
- Having a pre-dose sample (ideally within five minutes pre-dose) to determine the baseline value (often expected to be zero)..
- Frequent sampling around the predicted Tmax to ensure a reliable estimate
- Having at least three samples after Tmax to reliably estimate Ke.
- Having the last sample sufficiently distanced from time zero that the AUClast is at least 80% of the value of AUC0-∞.
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