THEORETICAL-STUDY OF THE INFLUENCE OF THE CIRCADIAN-RHYTHM OF PLASMA-PROTEIN BINDING ON CISPLATIN AREA UNDER THE CURVE

A mathematical model for area under the curve (AUC) determination is proposed taking into account the circadian variation of cisplatin protein binding. The main theoretical result obtained with the model is that early morning drug administration (2-4 AM) promotes the highest AUC. The model predicts a maximum AUC variation, due to the binding variation, ranging between 2.4 and 15%. The minimum of AUC between 2.45 and 3.30 PM is in agreement with the minimum nephrotoxicity observed when cisplatin is injected in the afternoon. The model can be applied to other drugs that are irreversively bound to proteins or irreversively bound to other plasma components if the binding rate depends on the time of day. The variation intensity of AUC was demonstrated to depend on drug characteristics, but can never be higher than the circadian variation of the protein binding rate.