JAC Advance Access originally published online on February 16, 2007
Journal of Antimicrobial Chemotherapy 2007 59(4):690-697; doi:10.1093/jac/dkl552
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Pharmacokinetic interaction between rifampicin and the once-daily combination of saquinavir and low-dose ritonavir in HIV-infected patients with tuberculosis
1 Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain 2 Pharmacy Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain 3 Infectious Diseases Unit, Hospital de Sant Pau, Barcelona, Spain 4 Clinical Biochemistry Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain 5 Internal Medicine Department, Hospital del Mar, Barcelona, Spain 6 Internal Medicine Department, Hospital Santa Caterina, Girona, Spain
Received 22 May 2006; returned 14 September 2006; revised 22 November 2006; accepted 20 December 2006
* Correspondence address. Servicio de Enfermedades Infecciosas, Hospital Universitari Vall Hebron, Paseo Vall Hebron 119-129, 08035 Barcelona, Spain. Tel: +34-934894497; Fax: +34-934282762; E-mail: eribera{at}vhebron.net
Objectives: 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 AUC0–24, Cmax and Ctrough, respectively, was seen with rifampicin and isoniazid. Ritonavir AUC0–24, Cmax and Ctrough 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.
Keywords: protease inhibitors , antiretroviral therapy , HIV infection , tuberculosis therapy
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