title: Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis.
abstract: 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.
authors.affiliation: Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain. eribera@vhebron.net
authors.forename: Esteban
authors.initials: E
authors.lastname: Ribera
authors.forename: Carlos
authors.initials: C
authors.lastname: Azuaje
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Lopez
authors.forename: Pere
authors.initials: P
authors.lastname: Domingo
authors.forename: Adria
authors.initials: A
authors.lastname: Curran
authors.forename: Maria
authors.initials: M
authors.lastname: Feijoo
authors.forename: Leonor
authors.initials: L
authors.lastname: Pou
authors.forename: Paquita
authors.initials: P
authors.lastname: Sánchez
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Sambeat
authors.forename: Joan
authors.initials: J
authors.lastname: Colomer
authors.forename: Josep Lluis
authors.initials: JL
authors.lastname: Lopez-Colomes
authors.forename: Manuel
authors.initials: M
authors.lastname: Crespo
authors.forename: Vicenç
authors.initials: V
authors.lastname: Falcó
authors.forename: Imma
authors.initials: I
authors.lastname: Ocaña
authors.forename: Albert
authors.initials: A
authors.lastname: Pahissa
mesh_terms: 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*
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D017320:HIV Protease Inhibitors; D019258:Saquinavir; D019438:Ritonavir; D012293:Rifampin