Delavirdine - Clinical pharmacokinetics and drug interactions

Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-I reverse transcriptase. The approved therapeutic regimen for delavirdine is 400mg 3 times daily in combination with appropriate antiretroviral agents; however, a dose of 600mg twice dail y appears to provide similar systemic exposure. The steady-state pharmacoki netics of delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with li ttle urinary excretion of unchanged drug. Metabolic drug interactions betwe en delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; delavirdine has no effect on the pharm acokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampi cin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, shoul d be avoided since delavirdine plasma concentrations are significantly lowe red. Reduction in gastric acidity (pH > 3) decreases the extent of delavird ine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of delavirdine by at least 1 h our. Delavirdine, unlike other currently available NNRTI agents, is an inhibitor rather than an inducer of CYP isozymes. Consequently, the drug interaction profile and rationale for combining delavirdine with other antiretroviral agents is unique among the current NNRTI agents. Delavirdine inhibits the C YP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of delavirdine to enh ance the pharmacokinetic profiles of protease inhibitors may permit the use of simplified administration regimens. Combining delavirdine and indinavir removes the food restrictions during indinavir administration. Furthermore , the superior virological response observed in antiretroviral regimens con taining delavirdine and protease inhibitors has been attributed to the favo urable pharmacokinetic interactions and the introduction of a new drug clas s in NNRTI-naive therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecti ng an HIV treatment regimen, due to the multiplicity of drugs that are coad ministered and the varying direction and magnitude of interaction that can occur. Considerations for utilising delavirdine in a treatment regimen are different than for other NNRTI agents due to the unique drug interaction pr ofile of delavirdine.