Pharmacological considerations in antiretroviral therapy

Suboptimum drug exposure arising from pharmacological and pharmacokinetic factors is an important reason that combination antiretroviral therapy fails in patients with human immunodeficiency virus type 1 infection. With all three available drug classes, the major causes are drug-drug interactions and interpatient pharmacokinetic variability. Inadequate concentrations of protease inhibitors and non-nucleoside reverse transcriptase inhibitors occur when concurrently administered drugs interfere with their metabolism by the hepatic cytochrome P450 enzyme system, the major metabolic pathway for these drugs. Combined therapy with certain nucleoside reverse transcriptase inhibitors can reduce systemic drug exposure by interfering with the intracellular conversion of administered drugs to their active metabolites. Important causes of interpatient variability in pharmacokinetic parameters include low oral drug bioavailability and individual differences in drug disposition and metabolism. Careful selection and monitoring of combination drug therapy along with individualized rather than standard dosage regimens may minimize these pharmacological problems and help ensure optimum antiviral activity.