Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. fluconazole clarithromycin or both brokers in combination. Data were obtained from stored samples collected during an earlier study that evaluated the pharmacokinetics of stavudine in the presence of multiple medications for opportunistic infections (7). The study was an open-label sequential randomized trial that enrolled 10 HIV-infected patients with a CD4 count of less than 200 cells/mm3 who were at least 18 years old and had no clinically significant renal or hepatic impairment. The study was reviewed by the National Institute of Allergy and Infectious Diseases Institutional Review Board and all patients provided written informed consent. Patients received Infectious Diseases Society of America-Centers for Disease Control WZ8040 and Prevention-recommended doses of either trimethoprim-sulfamethoxazole or aerosolized pentamidine for prophylaxis of pneumonia (10). Exclusion criteria included a history of allergies or adverse reactions to the study medications a history of peripheral neuropathy or uveitis laboratory values outside of protocol guidelines persistent diarrhea or malabsorption the use of brokers within 10 days of the study known to influence renal or hepatic metabolism or the usage of alcohol and drugs that could impair protection or conformity. Four medication regimens received at constant dosages: (i) rifabutin (300 mg once a time [q.d.]) by itself (ii) rifabutin and fluconazole (200 mg q.d.) (iii) rifabutin and clarithromycin (500 mg q.d.) and (iv) rifabutin fluconazole and clarithromycin. After getting rifabutin alone sufferers were randomly designated to take each one of the two-drug combos for seven days. The triple combination was administered last. In the seventh time of each program serial blood examples were gathered over 8 h with sampling moments of 0 h (predose) and 0.5 1 2 4 6 and 8 h postdose. Each regimen was followed by a 1-week wash-out period. All patients received each of the four regimens during the course of the study. The patients were allowed to take all medications with food. Rifabutin and 25-value of <0.05 was considered significant. Ten patients (9 male and 1 female) with an average age of 39 years (range 30 to 49) were enrolled in and completed the study. The mean baseline CD4 cell count percent CD4 cells and viral weight were 62 cells/mm3 (range 9 to 143) 6 (range 1 to 14) and 233 727 HIV RNA copies/ml (range <10 0 to 608 0 respectively. No significant alterations were observed in hepatic or WZ8040 renal function during the study. Since rifabutin is usually dosed as a once-daily regimen our 8-h sampling would not yield concentrations that are reflective Rabbit Polyclonal to RhoH. of levels in plasma for the entire dosing interval. A Bayesian approach was applied to simulate a 24-h dosing interval using a model with WZ8040 parameters for rifabutin from a previous study. By using this model and the previous data (6) as Bayesian priors we could achieve excellent fits of our data and accurately estimate a 24-h AUC. Rifabutin disposition was well explained by a two-compartment model with a lag time for absorption. The median = nonsignificant). The AUC of rifabutin with fluconazole and clarithromycin significantly increased 152 from baseline (= 0.002). TABLE 1 Pharmacokinetics of rifabutin in combination with clarithromycin and?fluconazole FIG. 1 Fitted concentration-time profiles of rifabutin (R) in combination with clarithromycin (C) and/or fluconazole (F). Other pharmacokinetic parameters of rifabutin (< 0.005). < 0.05). A nonsignificant (2.3-fold) increase was observed with fluconazole. Drug interaction studies WZ8040 examining two-drug combinations may not reflect the current clinical practice of HIV therapy and such studies cannot necessarily be extrapolated to patients on multiple medications. Three drugs that are often used in the management of opportunistic infections are rifabutin fluconazole and clarithromycin. Rifabutin is usually both an inducer and a substrate of the cytochrome P450 drug metabolism system specifically the CYP3A4 isoform. Fluconazole and clarithromycin are both inhibitors of CYP3A4. Given the shared.