DEVELOPMENT AND VALIDATION OF LIMITED-SAMPLING MODELS FOR THE ANTIRETROVIRAL AGENT ZIDOVUDINE

Limited-sampling strategies for zidovudine were studied in order to estimate the area under the concentration-time curve (AUC), the maximum plasma concentration (C(max)) and the plasma elimination half-life (t1/2) values of this antiretroviral agent. Six models, using 1 to 4 timepoints, were developed from a test data set of 42 patients. One model, consisting of 2 timepoints, t = 30 and t = 180 minutes after ingestion of zidovudine, and the zidovudine dose as an extra variable, appeared to be the best model for predicting AUC and C(max) values in a validation data set of another 41 patients. The proposed equations are: AUC (mg/L . h) = 0.0022 (h/L) . dose (mg) + 5.24 (h) . C180 (mg/L) + 0.39 (h) . C30 (mg/L); and: C(max) (mg/L) = 0.0022 (1/L) . dose (mg) + 2.11 . C180 (mg/L) + 0.93 . C30 (mg/L). In contrast, t1/2 values could not be predicted with acceptable confidence by any one of the models. However, during the terminal elimination phase, reliable t1/2 values could be obtained using only 2 timepoints (t = 120 and t = 180 minutes) to determine the zidovudine concentration. The proposed limited-sampling models can be of great value to obtain more insight into the relationships between the pharmacokinetic and pharmacodynamic properties of zidovudine, which are still poorly understood.