title: Delavirdine: clinical pharmacokinetics and drug interactions.
abstract: Delavirdine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a potent and specific inhibitor of HIV-1 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 daily appears to provide similar systemic exposure. The steady-state pharmacokinetics of delavirdine are not appreciably affected by food. Delavirdine undergoes extensive metabolism by cytochrome P450 (CYP) with little urinary excretion of unchanged drug. Metabolic drug interactions between delavirdine and nucleoside reverse transcriptase inhibitors are unlikely as their metabolic pathways differ; delavirdine has no effect on the pharmacokinetics of zidovudine. Concomitant use of CYP inducers, such as rifampicin (rifampin), rifabutin, phenytoin, phenobarbital or carbamazepine, should be avoided since delavirdine plasma concentrations are significantly lowered. Reduction in gastric acidity (pH > 3) decreases the extent of delavirdine absorption, so administration of antacids and the buffered formulations of didanosine should be separated from that of delavirdine by at least 1 hour. 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 CYP3A4-mediated metabolism of HIV protease inhibitors and thereby increases systemic exposure to protease inhibitors. The ability of delavirdine to enhance 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 containing delavirdine and protease inhibitors has been attributed to the favourable pharmacokinetic interactions and the introduction of a new drug class in NNRTI-naïve therapy-experienced patients. Pharmacokinetic drug interactions are an important consideration in selecting an HIV treatment regimen, due to the multiplicity of drugs that are coadministered 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 profile of delavirdine.
authors.affiliation: Agouron Pharmaceuticals, Inc., A Pfizer Company, La Jolla, California, USA. jonathan.tran@agouron.com
authors.forename: J Q
authors.initials: JQ
authors.lastname: Tran
authors.forename: J G
authors.initials: JG
authors.lastname: Gerber
authors.forename: B M
authors.initials: BM
authors.lastname: Kerr
mesh_terms: D020008:Delavirdine / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D054303:HIV Reverse Transcriptase; D006801:Humans; D007408:Intestinal Absorption; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine; D054303:HIV Reverse Transcriptase