ABSTRACT
OBJECTIVES: Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir. METHODS: In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718. RESULTS: In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated. CONCLUSIONS: The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Antitubercular Agents/pharmacokinetics , Drug Interactions , Healthy Volunteers , Pyrrolidinones/pharmacokinetics , Rifampin/analogs & derivatives , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Antitubercular Agents/administration & dosage , Antitubercular Agents/adverse effects , Female , Humans , Male , Plasma/chemistry , Pyrrolidinones/administration & dosage , Pyrrolidinones/adverse effects , Raltegravir Potassium , Rifampin/administration & dosage , Rifampin/adverse effects , Rifampin/pharmacokineticsABSTRACT
A new gas chromatographic/mass spectrometric (GC/MS) technique for the analysis of hydroxybenzenes (phenols) in mainstream cigarette smoke has been developed. The technique allows the measurement of 24 individual compounds, and the sum of a few other alkyl-dihydroxybenzenes. A critical evaluation is done for the new technique and for an established high-performance liquid chromatographic (HPLC) technique reported in the literature for the analysis of hydroxybenzenes in cigarette smoke, which uses fluorescence detection. Compared with the HPLC procedure, the new technique has similar accuracy, precision, and robustness. However, the GC/MS procedure allows for a larger number of phenols to be analyzed simultaneously, and eliminates any potential interference that may appear in the HPLC method. Using the GC/MS analysis, it was found that besides the main phenols typically measured in mainstream cigarette smoke such as phenol, catechol, hydroquinone, and cresols, many other phenols that are present at lower levels can be quantitated in mainstream cigarette smoke.
Subject(s)
Gas Chromatography-Mass Spectrometry/methods , Nicotiana/chemistry , Phenols/analysis , Smoke/analysis , Ascorbic Acid , Chromatography, Liquid , FluorescenceABSTRACT
A GLP-validated, sensitive and specific LC-MS-MS method for the quantification of paclitaxel and its 6-alpha- and 3'-p-hydroxy metabolites is presented. A 0.400 ml plasma aliquot is spiked with a (13)C(6)-labeled paclitaxel internal standard and extracted with 1 ml methyl-tert.-butyl ether. The ether is evaporated and the residue is reconstituted in 130 microl of 30% aqueous acetonitrile (ACN) containing 0.1% trifluoroacetic acid. Isocratic HPLC analysis is performed by injecting 50 microl of the reconstituted material onto a 50x2.1 mm C(18) column with an ACN-water-acetic acid (50:50:0.1) mobile phase at 200 microl/min flow. Detection is by positive ion electrospray followed by multiple reaction monitoring of the following transitions: paclitaxel (854>509 u), 6-alpha-hydroxy paclitaxel (870>525 u), 3'-p-hydroxy paclitaxel (870>509 u) and internal standard (860>509 u). Quantification is by peak area ratio against the 13C(6) internal standard. The method range is 0.117-117 nM (0.1-100 ng/ml) for paclitaxel and both metabolites using a 0.400 ml human or dog plasma sample. Analysis time per sample is less than 5 min.
