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 accur ate estimation of the area under the concentration time curve (AUC) when us ing the log trapezoidal method. Methods: A series of datasets were simulated. Each dataset comprised 1000 s ubjects. Each subject was "administered" an intravenous bolus dose of a dru g that displays two compartment pharmacokinetics. In the first series of si mulations, a variety of combinations of the number of sampling times (K) an d 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 t aken 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 variabi lity. 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 si milar accuracy to the conventional method. The best limited sampling combin ation was superior to the conventional method when assay variability was hi gh (CV = 30%), was similar when assay variability was 15%, but the conventi onal method became statistically superior when assay variability was 7.5% o r 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 i ncrease 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 te rms of sampling.