Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers.

STUDY DESIGN: Single centre, single ascending dose study. OBJECTIVES: To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. SETTING: Local population from Victoria, Australia. METHODS: Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. RESULTS: No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0-∞. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. CONCLUSION: Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure.

Is fosfomycin a potential treatment alternative for multidrug-resistant gram-negative prostatitis?

BACKGROUND: Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint ≤64 µg/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis. METHODS: In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery. RESULTS: Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 ± 7.6 µg/mL and 571 ± 418 µg/mL, 565 ± 149 minutes and 581 ± 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 ± 4.9 µg/g (range, 0.7-22.1 µg/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 ± 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 ± 6.6 vs PZ, 4.4 ± 4.1 µg/g; P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 µg/g, whereas the majority (70%) had concentrations ≥4 µg/g. CONCLUSIONS: Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required.