Having changed the landscape in the treatment of
HIV infection, the functional efficacy of current
protease inhibitors (PIs) remains limited by their pharmacokinetic and pharmacodynamic profiles. Complex metabolism by the
cytochrome P450 system (particularly the 3A4
isoenzyme), action of membrane
drug transporter elements (such as
P-glycoprotein and multi-drug resistance-associated
proteins) and activation of the
nuclear receptor steroid xenobiotic receptor may alter exposures and compromise the antiretroviral activity of these drugs. These factors, as well as inadequate adherence, can facilitate the emergence of PI resistance and lead to regimen failure. Coadministration of
ritonavir can enhance exposures of a primary PI by inhibiting
CYP3A4 metabolism,
P-glycoprotein activity and multi-drug resistance protein-1-mediated efflux. Adding
ritonavir, however, is not without cost. Dyslipidaemia (possibly increasing the risk of cardiovascular events), gastrointestinal intolerance, multiple
drug-to-drug interactions and activation of
steroid xenobiotic receptor can all result and must be balanced against the pharmacokinetic improvement rendered by the addition of
ritonavir. Understanding the pharmacological origins for the variations in exposures of PIs, both between and within patients, is important for the successful use of these agents.