Limited-sampling strategy models for estimating the area under the plasma concentration-time curve for amlodipine

Objective: Develop and validate limited-sampling strategy (LSS) models for estimating the area under the plasma concentration versus time curve (AUC) of amlodipine, using data from a bioequivalence study. Methods: Sixteen healthy volunteers received single 5-mg oral doses of amlo dipine, as reference or test formulation, at a 14-day interval, in a random ized, crossover protocol. Plasma concentrations of amlodipine (n = 288), me asured by mass spectrometry, were used to develop LSS models. Results: Linear regression analysis of the AUC(0-72) and a "jack-knife" val idation procedure revealed that LSS models based on two sampling times (12 h and 48 h) predict accurately (R-2 = 0.99; bias <0.01%; precision = 0.03%) the AUC(0-72) Of amlodipine for each formulation. Validation tests indicat e that the 2-point LSS model developed for the reference formulation predic ts accurately (R-2>0.90): (a) the individual AUC(0-72) for the test formula tion in the same group of volunteers; (b) the individual AUC(0-72) for the same reference formulation in another bioequivalence study in Brazilian vol unteers; (c) the average AUC(0-72) reported in seven additional internation al studies performed under protocols similar to the present investigation; (d) the individual AUC(0-72) corresponding to concentration data points pro vided by a first-order compartmental pharmacokinetic model, when the relati ve values of either the absorption rate (K-abs) Or the bioavailability (F) model parameters were set at 0.85 or 0.6, of their respective original valu es. Conclusions: The 2-point LSS models developed in the current study predict accurately the AUC of amlodipine under a variety of experimental conditions and, thus, may be valuable for exploring the relationships between the pha rmacokinetics and pharmacodynamics of this calcium antagonist, at reduced c osts of sample acquisition and analysis, and avoiding sampling at "unsociab le" hours.