Pharmacokinetic study of the interaction between rifabutin and delavirdine mesylate in HIV-1 infected patients.
The oxidative metabolism of delavirdine, a non-nucleoside inhibitor of HIV-1 reverse transcriptase, is mediated in part by cytochrome P450 3A. The influence of rifabutin, an inducer of certain human cytochrome P450 isozymes, on the steady-state pharmacokinetics of delavirdine was investigated in 12 HIV-positive patients with CD4 counts ranging from 75 to 671/mm3. Both the control group (n = 5) and the rifabutin group (n = 7) received 400 mg delavirdine mesylate every 8 h for 30 days; subjects in the rifabutin group took a 300 mg, once-daily dose of rifabutin on study days 16-30. 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 using a reversed-phase HPLC method. Blood samples obtained on days 16 and 30 were also assayed for rifabutin by HPLC. Delavirdine mesylate alone or in combination with rifabutin was well-tolerated. On day 30, statistically significant differences between groups were observed for all delavirdine pharmacokinetic parameters (P < 0.046). After coadministration of rifabutin and delavirdine mesylate for 2 weeks, oral clearance of delavirdine increased five-fold, resulting in lower steady-state plasma delavirdine concentrations. Rifabutin pharmacokinetic parameters were similar to those previously reported. Concomitant use of delavirdine and rifabutin at the recommended dose for each drug is discouraged. Maintaining therapeutic concentrations of delavirdine in patients on both medications may require dose modification.
Borin
M T
MT
Clinical Pharmacokinetics, Pharmacia and Upjohn Inc., Kalamazoo, MI 49001, USA.
Chambers
J H
JH
Carel
B J
BJ
Freimuth
W W
WW
Aksentijevich
S
S
Piergies
A A
AA
D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020008:Delavirdine; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism*; D015497:HIV-1; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017828:Rifabutin / Q000008:administration & dosage* / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D007211:Indoles; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D017828:Rifabutin; D003577:Cytochrome P-450 Enzyme System; D020008:Delavirdine; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating