Single-Dose Pharmacokinetics and Penetration of BMS 284756 into an Inflammatory Exudate

Abstract

The pharmacokinetics of a single dose of BMS 284756 were determined following oral administration of a 600-mg dose to eight healthy male volunteers. Concentrations of the drug were measured in plasma and a cantharidine-induced inflammatory exudate by a microbiological assay. The mean peak concentration in plasma of 10.4 g/ml (standard deviation [SD], 1.3 g/ml) was attained at a mean time of 1.2 h (SD, 0.5 h) after the dose. The penetration into the inflammatory exudate was 82% (SD, 15.7%). A mean peak concentration of 7.2 g/ml (SD, 2.4 g/ml) was attained in the inflammatory exudate at 5.3 h (SD, 1.5 h). The elimination half-lives from plasma and inflammatory fluid were 9.8 h (SD, 1.1 h) and 8.5 h (SD, 1.9 h), respectively. The areas under the concentration-time curves for plasma and inflammatory fluid were 96.7 g ⅐ h/ml (SD, 10.3 g ⅐ h/ml) and 77.9 g ⅐ h/ml (SD, 19.2 g ⅐ h/ml), respectively.BMS 284756 (T-3811ME) is a novel, orally and parenterally available, 6-des-fluorinated quinolone antimicrobial which displays a high degree of in vitro activity against a broad range of bacterial pathogens (1, 3). Preliminary data (D. A. Gajjar, D. M. Grasela, A. Bello, Z. Ge, and L. Christopher, 40th ICAAC, abstr. 2259, p. 36, 2000 suggest that the pharmacokinetics of this agent are dose related and that the elimination half-life supports a once-daily dosing regimen. There is little information on the ability of this agent to penetrate tissues. Here, we studied the pharmacokinetics of a single 600-mg oral dose in healthy adult volunteers and measured penetration into a cantharadine-induced inflammatory exudate (5).Eight healthy male volunteers, with a mean age of 28.1 years (range, 22 to 41 years), a mean weight of 78.4 kg (range, 73.6 to 84.9 kg), and a mean height of 178 cm (range, 173 to 185 cm) gave written informed consent to participate in this study following hospital ethics committee approval. Exclusion criteria for the study included any history of significant illness or atopy, recent participation in another drug trial, and the use of prescription or nonprescription drugs within 7 days of the study. All volunteers underwent a full medical history, examination, hematological and biochemical profiles, urinalysis, and drugsof-abuse screening prior to enrollment, all of which were normal. A 12-lead electrocardiogram (ECG) was performed on enrollment, within 24 h prior to dosing and 24 h postdose. The hematological and biochemical profiles were similarly repeated.The volunteers received 600 mg of BMS 284756 (as 200-plus 400-mg tablets) on the morning of the study following a 12-h overnight fast. The tablets were taken with 240 ml of water. The volunteers received only clear fluids for 2 h thereafter, and then a full diet was resumed.Two 0.2% cantharidine-impregnated plasters were placed on the volunteers' forearms about 12 h prior to drug administration, in order to induce blister formation. Blood (10 ml) and inflammatory fluid (50 l) samples were taken at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h postdose.A microbiolog...

Antimicrobial Activities of Garenoxacin (BMS 284756) against Asia-Pacific Region Clinical Isolates from the SENTRY Program, 1999 to 2001

“…It is therefore likely that staphylococcal fluoroquinolone resistance will persist in the Asia-Pacific region. Whether an agent such as garenoxacin has less potential to select for resistant mutants and therefore maintain clinical utility is unclear, but its high potency compared to its pharmacokinetics (35) suggests that this may be the case.…”

Moxifloxacin Versus Cephalexin in the Treatment of Uncomplicated Skin Infections

“…A clinical study of moxifloxacin distribution in healthy human volunteers by investigation of cantharides-induced inflammatory exudate demonstrated that following a single oral or IV dose (400 mg), moxifloxacin penetrates rapidly into the site of an inflamed lesion. 15 The concentration of moxifloxacin in plasma versus inflammatory exudate reached a C"'"' of 4.9 vs 2.8 mg/I at approximately I vs 3.1 hours post oral dose. The half-life was 8.3 vs IO hours over the study time and achieved an AUC of 39.0 vs 32.5 mg/1/h.…”

Acyclovir concentrations in the skin of humans after a single oral dose assessed by in vivo cutaneous microdialysis

“…To evaluate this parameter, several experimental models have been elaborated. Among skin blisters developed either by using mild suction (13–15) or by direct application to the skin, an irritating agent – cantharidin – in the form of a plaster (16, 17) or ointment (18, 19) containing 0.2–0.25% of this compound, have been used more frequently todate.…”