Principles and practice of HIV‐protease inhibitor pharmacoenhancement

Continually maintaining maximally suppressive drug concentrations represents a key defence against the emergence of resistance. If drug levels fall and replication occurs, the opportunity for mutant virus to be selected occurs. It has been increasingly recognized that variability in the pharmacokinetics of antiretrovirals, particularly protease inhibitors (PIs), means that drug exposure is not always optimal, giving the virus a chance to replicate.A significant number of patients receiving PIs two or three times daily will have trough (Ctrough or Cmin) plasma concentrations, which are close to, or below, the plasma protein binding‐corrected inhibitory concentration (IC50 or IC95) during the dosing interval. It is primarily in this context that therapeutic drug monitoring of PIs has been proposed as an aid to patient management, to ensure that patients maintain adequate drug concentrations throughout the dosing interval. Ideally, an antiretroviral drug will have a pharmacokinetic (PK) profile that maintains drug levels well above the viral inhibitory concentration throughout the entire dosing interval.Beneficial drug–drug interactions have been shown to improve PI pharmacokinetics.