Phosphorylation of Zidovudine When Dosed in an In Vitro Pharmacodynamic System That Simulates In Vivo Pharmacokinetics

This team have developed a cell culture system in which drugs can be administered so as to mimic human pharmacokinetics. In this study with AZT, the relationship between AUC of AZT in plasma and of AZT-TP inside the cell was investigated. This showed that, with once daily dosing, the equivalent of twice the plasma AUC was required to give the same AUC for AZT-TP as from continuous infusion.

Similarly, continuous infusion was more inhibitory to HIV replication than once daily dosing. Simulated plasma AUC of 0.001 umole . h/L from iv infusion was as active as 0.3 umole . h/L from once daily dosing.

This is a direct illustration that the plasma drug trough level seems to be a key factor for failure in the control of HIV replication.