Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.
OBJECTIVE
To assess plasma steady-state pharmacokinetics (PK) of rifampicin, isoniazid, saquinavir and ritonavir in HIV and tuberculosis (TB) co-infected patients, and investigate potential interactions between TB drugs and protease inhibitors (PIs).


METHODS
Open-label, single-arm, sequential PK study including 22 patients with HIV infection and TB. During the first 2 months, patients received rifampicin, isoniazid and pyrazinamide, with or without ethambutol (first PK study, n = 22). Then patients stopped pyrazinamide and ethambutol and started once-daily antiretroviral therapy (ART) with didanosine, lamivudine, ritonavir (200 mg) and saquinavir (1600 mg) (second PK study, n = 18). Patients stopped all TB drugs after 9 months continuing the same ART (third PK study, n = 15). Differences between TB drug parameters in the first and second PK studies, and between PI parameters in the second and third PK studies were used to assess interactions.


RESULTS
Rifampicin and isoniazid pharmacokinetics did not change substantially with saquinavir and ritonavir. A significant 39.5%, 34.9% and 48.7% reduction in median saquinavir AUC(0-24), C(max) and C(trough), respectively, was seen with rifampicin and isoniazid. Ritonavir AUC(0-24), C(max) and C(trough) decreased 42.5%, 49.6% and 64.3%, respectively, with rifampicin and isoniazid.


CONCLUSIONS
There was a significant interaction between saquinavir, ritonavir and rifampicin, with reduction in median plasma concentrations of saquinavir and ritonavir. Saquinavir should be given with caution in patients receiving rifampicin. Twice-daily dosing or higher saquinavir doses in once-daily administration should be tested to obtain more appropriate plasma levels.
Ribera
Esteban
E
Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain. eribera@vhebron.net
Azuaje
Carlos
C
Lopez
Rosa M
RM
Domingo
Pere
P
Curran
Adria
A
Feijoo
Maria
M
Pou
Leonor
L
Sánchez
Paquita
P
Sambeat
Maria Antonia
MA
Colomer
Joan
J
Lopez-Colomes
Josep Lluis
JL
Crespo
Manuel
M
Falcó
Vicenç
V
Ocaña
Imma
I
Pahissa
Albert
A
D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D015233:Models, Statistical; D012293:Rifampin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019258:Saquinavir / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013056:Spectrophotometry, Ultraviolet; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*
D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D017320:HIV Protease Inhibitors; D019258:Saquinavir; D019438:Ritonavir; D012293:Rifampin