Development of a general method of limited sampling for the determination of AUC for a drug that displays two-compartment pharmacokinetics

Objectives: To develop a method of limited sampling that would enable accurate estimation of the area under the concentration time curve (AUC) when using the log trapezoidal method. Methods: A series of datasets were simulated. Each dataset comprised 1000 subjects. Each subject was "administered" an intravenous bolus dose of a drug that displays two compartment pharmacokinetics. In the first series of simulations, a variety of combinations of the number of sampling times (K) and number of replicate measurements (R) at each of these times were tested, where K x R = 12 (i.e. N = 12). The times that each of the K samples were taken were chosen to be those that divided the AUC into K - 1 trapezoids of equal area. The concentration-time curves were estimated based on a priori estimates of the population parameters. The best combination of K and R was tested under various conditions of parameter variability and assay variability. The combinations were compared with a conventional sampling strategy, where N = 12, K = 12(R = 1). Results: The combination K = 4 and R = 3 proved to be the "best". It had similar accuracy to the conventional method. The best limited sampling combination was superior to the conventional method when assay variability was high (CV = 30%), was similar when assay variability was 15%, but the conventional method became statistically superior when assay variability was 7.5% or less. The accuracy of the best limited sampling combination was inversely related to the parameter variability. If K was set to 4 and R allowed to increase to 6 (i.e. N not equal 12), there was no further gain in accuracy. Conclusion: The proposed method of limited sampling is at least as accurate as the conventional intensive sampling technique, but more efficient in terms of sampling.