Bioavailability Study of Menorest®, a New Estrogen Transdermal Delivery System, Compared with a Transdermal Reservoir System.

The aim of this study was to compare the bioavailability and plasma profiles of estradiol and estrone after repeated applications of 2 types of estradiol transdermal systems: a new adhesive matrix system (Menorest®) compared with a reference membrane/reservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomised, crossover study, with 2 treatment periods of 10.5 days separated by a 10-day washout period and with a 1-week follow-up. Participants were studied at Institut Aster, Paris, and Association de Recherche Thérapeutique (ART), Lyon, France, and included 31 healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean 58 years). Each transdermal system was applied for three successive 3.5 day-wear periods (10.5 days) on the lower abdominal skin. Plasma estradiol and estrone concentrations were measured at steady-state, before and after the third application of each transdermal system at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. Although the extent of availability [area under the plasma concentration-time curve (AUC) and average plasma concentration (Cav)] was similar with both transdermal systems, their pharmacokinetic profiles were different, with Menorest® producing less fluctuating and more sustained plasma estradiol levels than the reference system. The mean estradiol to estrone Cav ratio was similar with the 2 transdermal systems and in the physiological range of premenopausal status. The incidence of adverse events was similar for both treatments, but a lower incidence of local erythema was observed with Menorest® (8.9%) than with the reference system (18.3%). In conclusion, during the entire wear period, Menorest® produced more sustained plasma estradiol levels with less fluctuations (40 to 72 ng/L) than the reservoir/ membrane system (18 to 102 ng/L). Menorest® gave estradiol plasma levels approximating the concentrations observed during the early to mid-follicular premenopausal stage, with a 2-fold lower incidence of erythema than with the reservoir/membrane system.

Pharmacokinetics of spiramycin in man.

The pharmacokinetics of spiramycin were studied after single and repeated administration by iv and oral routes. Following iv administration of a 500-mg dose in a one-hour infusion, peak serum concentrations were 1.54-3.10 mg/l. These concentrations are higher than MICs of spiramycin for various infectious agents. Eight hours after the end of infusion, the mean serum concentration was close to 0.25 mg/l. Spiramycin is rapidly and widely distributed throughout the body and achieves high ratios of tissue to serum concentrations in bucco-dental, pulmonary and prostatic tissues and skin. The distribution half-life of spiramycin was 10 min. The steady-state volume of distribution (Vdss) and the tissue distribution volume were 5.6 and 4.5 l/kg. The absolute bioavailability of spiramycin was 36% (S.D. +/- 14). Oral doses of spiramycin between 1 and 2 g resulted in linear increase in the peak serum levels and areas under the serum concentration-time curve. Spiramycin does not appear to undergo important metabolic conversion and is mainly excreted via the biliary route. Indeed, in man, the urinary excretion of active compounds represents only 7.6 to 20% of the administered dose. Spiramycin had a terminal elimination half-life of approximately 5 h. Renal clearance (144 ml/min) was much lower than non-renal clearance (887 ml/min). The total body clearance of spiramycin in young adults was 1.42 l/min (S.D. +/- 0.5) but only 0.53 l/min (S.D. +/- 14) in elderly subjects. During repeated iv administration (500 mg tid), steady state was achieved after four doses. Cmax and Cmin were 3.0 and 0.5 mg/l in young adults and 4.5 and 1.75 mg/l in elderly patients. Spiramycin's kinetics differ in several important respects from erythromycin's, notably the larger volume of distribution of spiramycin which reflects the higher tissue concentration. The reduced spiramycin clearance in elderly subjects requires further investigation.

Pharmacokinetics of pefloxacin after repeated intravenous and oral administration (400 mg bid) in young healthy volunteers.

Multiple-dose kinetics of pefloxacin was determined in 12 normal male subjects given 400 mg pefloxacin by iv 1 h-infusion every 12 h for 16 doses. Twelve other subjects (6 men and 6 women) were given 400 mg pefloxacin by mouth every 12 h for 18 doses. Plasma and urine concentrations of pefloxacin and its main metabolites (N-desmethyl pefloxacin or norfloxacin and pefloxacin N-oxide) were measured by high performance liquid chromatography. The bioavailability of pefloxacin was complete and plasma concentrations after iv or oral administration were similar. Pefloxacin was rapidly absorbed from the gastrointestinal tract and reached maximum plasma concentrations about 1 h after dosing. Pefloxacin elimination (T 1/2 beta) increased from 11.00 +/- 2.64 h after the first iv dose to 13.93 +/- 3.58 h after the last iv dose (P less than 0.01). Apparent total body clearance decreased from 148.5 +/- 47.6 to 106.9 +/- 39.2 ml/min (P less than 0.01) because of decreased non-renal clearance (apparent volume of distribution did not significantly change over the repeated pefloxacin administration). Similar results were obtained after repeated oral dosing. Renal clearance of pefloxacin was low (7.47 +/- 2.28 ml/min) indicating that non-renal clearance represents the major route of elimination of this quinolone. Urinary excretion of pefloxacin and N-desmethyl and N-oxide metabolites was approximately 31% of the pefloxacin dose and beta-elimination half-lives of these metabolites were very close to that of pefloxacin (13.34 +/- 2.72 h and 11.95 +/- 2.64 h respectively). Due to a possible saturable process in the metabolic pathway, some accumulation occurred during repeated iv or oral treatment (accumulation ratio = 1.37 +/- 0.20). These results show that concentrations of pefloxacin in excess of the minimum inhibitory concentrations for many important pathogens can be rapidly achieved in plasma and urine with the 400 mg bid regimen with both iv and oral routes.

Transfer kinetics of pefloxacin into cerebro-spinal fluid after one hour i.v. infusion of 400 mg in man.

Nine subjects (5 women) aged between 17-66 years, with hydrocephalus were studied. An external ventricular drain was introduced for diagnostic purposes. Cerebro-spinal fluid (CSF) and plasma samples were obtained at suitable intervals after 1 h infusion of 400 mg pefloxacin. In plasma, pefloxacin Cmax was 8.54 +/- 1.53 (mean +/- S.E.M.) mg/l, at the end of infusion, whereas N-desmethyl pefloxacin concentration was 0.17 +/- 0.03 mg/l. The metabolite accounted for only 2% of plasma levels of pefloxacin. In CSF, pefloxacin Cmax was 2.97 +/- 0.32 mg/l, 5-6 h after the start of infusion, whereas N-desmethyl pefloxacin Cmax varied between 0.1-0.2 mg/l. Apart from the 1 h sample, the CSF/plasma ratio of pefloxacin was 60% which is similar to the unbound fraction of pefloxacin in plasma. The apparent half-life (T1/2) of transfer of pefloxacin from plasma to CSF was 1.26 +/- 0.18 h, assuming a first order process, while the apparent elimination T1/2 in CSF was 13.40 +/- 1.76 h, which is similar to the elimination T1/2 found previously in plasma, thus accumulation of pefloxacin in CSF is unlikely. With the present dosage regimen, CSF quickly attains therapeutic levels of pefloxacin.