Pharmacokinetic study of the interaction between rifampin and delavirdine mesylate

Clin Pharmacol Ther. 1997 May;61(5):544-53. doi: 10.1016/S0009-9236(97)90134-X.

Abstract

Objective: To study the effect of rifampin (INN, rifampicin), a potent inducer of cytochrome P450, on the steady-state pharmacokinetics of delavirdine.

Methods: Twelve patients who were positive for human immunodeficiency virus, with CD4 counts ranging from 110 to 483/mm3, were randomized to two groups and studied in parallel. Both the control group (n = 5) and the rifampin group (n = 7) received 400 mg delavirdine mesylate every 8 hours for 30 days; subjects in the rifampin group took a 600 mg once-daily dose of rifampin on days 16 through 30. Harvested plasma from serial blood samples collected after dosing on days 15, 16, and 30 was assayed for delavirdine and its N-desalkyl metabolite concentrations with a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifampin by HPLC.

Results: Delavirdine mesylate alone and in combination with rifampin was well tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (p < 0.049). In the rifampin group, delavirdine oral clearance increased by about 27-fold (p = 0.022), resulting in virtually negligible (< 0.09 mumol/L) steady-state through drug concentrations in all patients after 2 weeks of concurrent dosing of delavirdine mesylate and rifampin. The ratio of metabolite formation to elimination clearance for desalkyldelavirdine was significantly higher (3.9 +/- 1.2 versus 0.23 +/- 0.10) and delavirdine elimination half-life was significantly shorter (1.7 +/- 1.4 versus 4.3 +/- 1.3 hours) when delavirdine mesylate was taken with rifampin. Rifampin pharmacokinetic parameters on days 16 and 30 were similar to those previously reported for normal volunteers.

Conclusions: The findings of this study indicate that rifampin induces the metabolism of delavirdine. Therefore therapy with rifampin is contraindicated in patients receiving delavirdine mesylate.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Alkylation
  • Anti-HIV Agents / blood
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Antibiotics, Antitubercular / administration & dosage
  • Antibiotics, Antitubercular / blood
  • Antibiotics, Antitubercular / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases*
  • Blotting, Western
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / drug effects
  • Cytochrome P-450 Enzyme System / metabolism
  • Delavirdine
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • HIV Seropositivity / blood
  • HIV Seropositivity / drug therapy
  • HIV Seropositivity / metabolism*
  • Humans
  • Hydrocortisone / analogs & derivatives
  • Hydrocortisone / blood
  • Indoles / blood
  • Indoles / pharmacokinetics*
  • Indoles / therapeutic use
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Middle Aged
  • Oxidoreductases, N-Demethylating / drug effects
  • Oxidoreductases, N-Demethylating / metabolism
  • Piperazines / blood
  • Piperazines / pharmacokinetics*
  • Piperazines / therapeutic use
  • Reverse Transcriptase Inhibitors / pharmacokinetics*
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Rifampin / administration & dosage
  • Rifampin / blood
  • Rifampin / pharmacokinetics*

Substances

  • Anti-HIV Agents
  • Antibiotics, Antitubercular
  • Indoles
  • Piperazines
  • Reverse Transcriptase Inhibitors
  • 6 beta-hydroxycortisol
  • Cytochrome P-450 Enzyme System
  • Delavirdine
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Rifampin
  • Hydrocortisone