Investigations on dose proportionality and drug-drug interaction for a fixed-dose combination of trazodone and gabapentin.

OBJECTIVES: To establish dose proportionality for trazodone and gabapentin at fixed ratios of trazodone/gabapentin 2.5/25, 10/100, and 30/300 and investigation of potential drug-drug interaction at a dose of 10/100. MATERIALS AND METHODS: 29 out of 30 healthy subjects completed this single-center, open-label, randomized, 5-period cross-over trial with single-dose fasted administrations. Administrations were separated by a washout period of at least 6 days. Blood samples were drawn until 48 hours post dose. A validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) was applied for determination of trazodone and gabapentin in plasma. The lower limits of quantitation (LLOQ) were 1.00 ng/mL and 5.00 ng/mL for trazodone and gabapentin, respectively. Adverse events (AEs) were analyzed in the study population descriptively. RESULTS: Plasma concentrations were characterized thoroughly. For trazodone, assessment of proportionality (power model/pairwise-comparison by ANOVA) showed proportionality for AUC over all doses and for Cmax between the middle and high dose. For gabapentin, a less than proportional increase in both metrices was present with a likely proportional increase from 25 to 100 mg only. Considering common bioequivalence criteria, absence of pharmacokinetic interaction was confirmed comparing the combination and individual agents. 23 subjects experienced 53 AEs during the trial, the most frequent being fatigue (20 cases/15 subjects) and dizziness (14 cases/11 subjects). No serious AEs were reported. CONCLUSION: To our knowledge, for the first time, proportionality for trazodone at doses of 2.5 to 30 mg and for gabapentin at doses of 25 to 300 mg was investigated. Absence of a pharmacokinetic interaction was shown.

Penetration of orally administered prulifloxacin into human prostate tissue.

BACKGROUND AND OBJECTIVE: Prulifloxacin, a fluoroquinolone antibacterial agent, may be a useful addition to the antimicrobial armamentarium against prostatitis once the ability of its active metabolite, ulifloxacin, to penetrate prostatic tissue has been determined. This study set out to evaluate ulifloxacin penetration into the prostate following administration of the oral fluoroquinolone prodrug prulifloxacin in patients undergoing transurethral resection of the prostate (TURP). METHODS: This was a phase I, randomized, open-label, single-centre study involving 20 male Caucasian patients (mean age 63.1 years) requiring TURP for treatment of benign prostatic hyperplasia. Sixteen patients were randomized to receive prulifloxacin; the other four patients were not treated (controls) in order to validate the bioanalytical method. Patients in the active treatment groups were randomized to receive one or three once-daily doses of prulifloxacin 600 mg, with the last administration 3 hours prior to surgery. Central/transitional and peripheral zone prostatic tissue samples were obtained from the 6 o'clock and 9 o'clock positions in the prostate, and blood samples were collected concurrently. Ulifloxacin concentrations were determined in the tissue samples and plasma using liquid chromatography-tandem mass spectrometry. Safety was also assessed. RESULTS: Prostatic tissue concentrations of ulifloxacin always exceeded those in plasma. Mean ulifloxacin concentrations measured in samples collected from the 6 o'clock central/transitional zone of the prostate were higher in patients who received prulifloxacin for 3 days than in those who received a single dose. Mean prostatic tissue/plasma ulifloxacin concentration ratios after single and repeated prulifloxacin administration ranged from 3.8 to 7.1 and from 3.9 to 9.5, respectively. The highest mean ratio was found in the 6 o'clock central/transitional zone after repeated dosing. Prostatic levels of ulifloxacin were above the minimum inhibitory concentrations for the most common causative pathogens of bacterial prostatitis. No treatment-related toxicities were reported. CONCLUSION: These findings confirm the ability of prulifloxacin to penetrate prostatic tissues, indicating high exposure of the target tissue to ulifloxacin and, therefore, a potential therapeutic role for prulifloxacin in the treatment of bacterial prostatic infections.