Effectiveness of Alora estradiol matrix transdermal delivery system in improving lumbar bone mineral density in healthy, postmenopausal women.

OBJECTIVE: To determine the lowest effective dose of an estradiol (E ) matrix-type transdermal delivery system (EMTDS; Alora) for preventing bone loss in postmenopausal women. DESIGN: This double-blind, double-dummy, randomized, placebo-controlled, multicenter study enrolled 355 nonosteoporotic postmenopausal women who had been hysterectomized with or without oophorectomy at least 12 months earlier. Participants were randomly assigned to one of three doses of the EMTDS (0.025, 0.05, or 0.075 mg/day) or placebo administered twice weekly. Lumbar bone mineral density (LBMD) was measured by dual-energy x-ray absorptiometry at screening and after 1 and 2 years of treatment. Safety was assessed at regularly scheduled visits. RESULTS: EMTDS provided statistically significant and clinically meaningful changes in LBMD relative to placebo. At 2 years, LBMD declined from baseline by 0.59% in the placebo group, but it increased from baseline by 1.65% ( = 0.0065), 4.08% ( = 0.0001), and 4.82% ( = 0.0001) in the EMTDS 0.025, 0.05, and 0.075 mg/day groups, respectively. The corresponding responder rates (defined as no change or increase in LBMD at endpoint) were 39.7% for placebo, 59.6%, 79.3%, and 83.9% in the EMTDS 0.025, 0.05, and 0.075 mg/day groups, respectively. Mean serum E concentrations were proportional to the dose of the E transdermal system and did not accumulate over the course of the study. Adverse events were generally comparable across treatment groups, with the majority being mild or moderate in severity and unrelated to study medication. Mammogram findings and other safety assessments were also comparable across groups and did not reveal any safety concerns with 2-y transdermal E treatment. CONCLUSIONS: The EMTDS (Alora) administered twice weekly improves lumbar bone mineral density in healthy postmenopausal women, with the benefit of treatment evident by 1 year. The lowest effective dose is 0.025 mg/day.

Pharmacokinetics of a New Anticonvulsant (CGP 33101) in Epileptic Male Patients and Healthy Male Subjects after Single Ascending Oral Doses of 400--1200 mg.

Information on the pharmacokinetic behavior of a new anticonvulsant agent (CGP 33101) was obtained after oral administration of ascending doses to male epileptic patients maintained on existing antiepileptic drug (AED) therapy, as well as to healthy male subjects. Single doses of 400, 800 and 1200 mg were administered to 12 of the 16 epileptic patients participating in the clinical trial and all 3 healthy subjects; the remaining patients received placebo doses on each dosing occasion. The study's primary objectives were to obtain single-dose add-on tolerability information, as well as preliminary pharmacokinetic data for the drug candidate. Either placebo or 400, 800 and 1200 mg of the compound, administered as 200-mg tablets, were coadministered with enzyme-inducing antiepileptic medications to the patients participating in the trial. These AEDs dilantin, tegretol, depakote, mysoline and tranxene) were administered individually or as combination therapy of two or three, with each patient being on the existing therapy for a minimum of 3 weeks prior to receiving the drug candidate (CGP 33101) as an add-on. Three healthy male subjects were included in the study to provide concurrent pharmacokinetic data at equivalent doses, as well as additional safety data in the absence of concomitant medication. Plasma concentrations of the new drug candidate were determined in samples obtained predose through 120-h postdose, with a 5-day washout period between doses. Preliminary pharmacokinetic parameters, such as peak plasma concentrations (C(max), times to peak levels (T(max)), areas under the plasma concentration-time curve (AUC) and terminal half-lives (T(1/2)), were determined in both epileptic patients and healthy subjects following all three doses. The mean T(max) values were similar for all three dose levels in both patients and subjects, indicating that the rate of absorption was comparable. Mean C(max) values increased in a dose-related manner with increasing dose in epileptic patients. The corresponding values showed a dose-proportional relationship in healthy subjects. The relationship between C(max) values and the administered dose did not change in patients or subjects when the data was corrected for dose and/or body weight. After the peak, plasma levels declined, but were still quantifiable in most patients and subjects at 36 h following all three doses. The mean AUC values increased in a dose-proportional manner with increasing dose in healthy subjects. The corresponding mean patient data appeared to increase in a dose-related manner. The relationship between AUC values and size of the administered dose did not change in either patients or subjects when the data was corrected for dose and/or body weight. The terminal elimination half-lives (T(1/2)) were apparently shorter in patients compared to the healthy subjects and were independent of the close administered.

Application of a Stable Isotope Technique for the Bioequivalency Study of Two Transdermal Nitroglycerin Systems.

A bioequivalency study of an experimental transdermal nitroglycerin system relative to the commercial Transderm-Nitro 0.4 mg/h system was performed on eight healthy volunteers by using an innovative stable isotope technique. Plasma clearance changes for nitroglycerin (NTG) during patch application were corrected with simultaneously administered intravenous infusion of (15)N-labeled nitroglycerin ((15)N-NTG) solution. The total amount of NTG transdermally absorbed (AUC x CL) during a 22-h application for the experimental system was not statistically different from that for the commercial system (9.7 plus minus 3.3 versus 8.1 plus minus 2.6 mg; p = 0.41). The analysis of residual drug content in the used system revealed that the difference in amounts of NTG delivered from the experimental and commercial systems were not significant (12.2 plus minus 3.1 versus 10.8 plus minus 3.1 mg; p = 0.29). With the isotope-labeled method, the absorption rate was evaluated at each time interval during the system application. The peak concentration values were 0.52 plus minus 0.21 mg h(minus sign1) at 1 h for the experimental system and 0.41 plus minus 0.15 mg h(minus sign1) at 2 h for commercial systems. After the peak concentrations, the absorption rates remained constant for both systems over the 16-h period. There was no statistical difference in absorption between the two systems at any sampling time. In this study, substantial fluctuations in the plasma concentrations of both NTG and (15)N-NTG were observed within and between subjects. In addition, the variability in plasma concentrations of NTG correlated well with that of (15)N-NTG for all participating subjects. The momentary changes of clearance, estimated from (15)N-NTG plasma data, were found to be responsible for the fluctuation of NTG in plasma.