Article

17β‐Estradiol Matrixpatch Removal and Reapplication in Postmenopausal Women: Experimental Results

Authors:
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

This study compares the pharmacokinetic performance of a matrix system for transdermal 17-beta-estradiol (E(2)) delivery using multiple consecutive dosing with a first application in postmenopausal women undergoing hormone replacement therapy. A clinical study (SI) was conducted over a treatment period of 11 days in 16 postmenopausal women receiving three consecutively applied matrix patches for the delivery of E(2). The first patch was worn for 4 days, the second for 3 days, and the third patch for 4 days. The E(2) plasma profiles determined during the third application were compared with results obtained by a published clinical study (SII) using the same patch in the same group of postmenopausal women without E(2) pretreatment. Additionally, the 24 h plasma profiles of E(2) and estrone were determined before and on day 4 during patch application of the third patch. Comparison of the mean pharmacokinetic parameters from the two studies showed no significant difference in E(2) plasma levels: AUC(0-->96h) [pg/mL h] SI: 4342 +/- 1513 and SII: 4512 +/- 1229; C(max)[pg/mL] SI: 51.3 +/- 28.8 and SII: 54.2 +/- 22.3; C(average) [pg/mL] SI: 45.0 +/- 13.2 and SII: 47.0 +/- 9.4; C(min) [pg/mL] SI: 31.4 +/- 5.9 and SII: 32.2 +/- 8.1. Over 96 h, fluctuation, f, defined as (C(max) - C(min)) / C(average), was 0.44 in SI and 0.47 in SII. Individual comparison of E(2)-C(max), -AUC, and -C(min) revealed that more than 87.5% of all patients showed a variation between SI and SII of less than 10%. The mean of the individual AUC(0-->96h) variation between the first and the third patch was only 4.7%. There was no significant drop in E(2) plasma values after patch removal and reapplication, and accumulation of E(2) did not occur after several patches were applied consecutively. Plasma E(2) showed a circadian rhythm that was lower in the morning and higher in the evening. No circadian rhythm was observed in untreated basal plasma E(2) in the group of postmenopausal women. The transdermal matrix system yielded sustained E(2) plasma levels in postmenopausal women in the initial application period. In long-term dosing there was no accumulation of E(2) in plasma and no significant drop after patch removal. It is presently not known why the circadian variation in the experimentally obtained E(2) plasma values exists.

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... As there is a newly sparked interest in E2 delivery, several questions still remain concerning E2 steady state delivery, the relationship between pharmacokinetics and dynamics, as well as a comparison between oral and transdermal pharmacokinetics and pharmacodynamics. Previously we published the pharmacokinetic of transdermal delivery with a matrix patch [4,5]. We reported a surprise finding that the transdermal delivery of E2 by a matrix patch steady state condition is achieved within the first matrix patch application, which was later corroborated for a contraceptive patch containing E2 that utilized the same matrix technology [6]. ...
... We therefore decided to investigate the steady state condition for immediate oral delivery. In contrast to our previous steady state investigation with a matrix patch for Table 1 Key characteristics of participating menopausal women [3,4,12]. ...
... The pharmacokinetic analysis is difficult because circadian E2 plasma rhythms exist in premenopausal women and the transdermal and ovarian uptake may be partially influenced by blood perfusion [4,5]. It is therefore of interest whether circadian plasma values exist for oral delivery too. ...
Article
There is a renewed interest in the delivery of estradiol (E2) for the reduction of menopausal symptoms in young symptomatic menopausal women. This paper compares experimentally and theoretically obtained E2 plasma values by oral and transdermal delivery and compares them with relevant menopausal symptoms. Two independent previously published studies were compared, which each contained 42 young symptomatic menopausal women. Experimentally obtained plasma values at days 1, 7 and 21 were compared with a theoretical model, taken from the literature, for describing plasma values for an oral immediate release formulation, consecutively for 21 days. Menopausal symptoms were determined in the steady state for oral and transdermal delivery with the Kuppermann index, previously not reported. In the case of oral delivery, estradiol was compared with estradiol valerate. Previously published results for transdermal delivery of E2 showed that the matrix system establishes a steady state condition with the application of the first patch. Excellent agreement between theoretically predicted and experimentally obtained E2 plasma values for oral delivery in menopausal women was obtained. Circadian E2 plasma levels were observed continuously for transdermal delivery, were seen in oral delivery during first application and disappeared when steady state was achieved. Application of the prodrug E2-valerate delayed the maximum plasma peak from 1 pm to 4 pm, similar to the transdermal matrix patch. Investigating menopausal symptoms determined with the Kuppermann index did not reveal differences between oral or transdermal “E2 kinetic (hot flushes) relationship”. This relationship was similar to symptomatic women suffering from hot flushes in untreated menopausal women or premenopausal women. Different menopausal symptoms required different E2 plasma levels: the average E2 levels higher than 23 pg/mL in plasma did abolish insomnia in 50% of postmenopausal women, with 28 pg/mL is needed to suppress 50% of dysthymia; however, rather high levels of 41 pg/mL are needed to suppress 50% of hot flushes, suggesting a rather complex mechanism beyond an E2 receptor mediated process. There is a difference in the steady state between oral and transdermal E2 delivery. Steady state condition is achieved in the first application of a matrix patch, whereas with the application of a tablet the steady state is achieved in transdermal delivery within 12–14 days. Our reported calculated missed intake of a E2 tablet shows that E2 plasma levels drop for 4 days consecutively. Our conducted study has several limitations: firstly, no cross-over was conducted, but a rather cumbersome mathematical modeling; secondly, healthy women with no accompanying severe diseases were included in this study. The higher the oral dose, the higher the E2 steady state levels, but the time to achieve steady state levels is independent from the E2 dose.
... This metric would help estimate when to replace the monolithic patch. Research shows that repeated applications of the device can be used as a strategy to maintain a steadystate flux [7], leading to an effective drug concentration in the blood stream [8,9]. Similar to the TDDS 1 device, a single time constant can also be derived to predict the time (t eff ) it takes to release the drugs from the matrix. ...
... Considering that: Product designers can use the effective time constant to estimate the performances of TDDS 1 and TDDS 2. The method provides manufacturers with an analytical tool to help estimate the time it takes the medication to begin working after the application of a patch of type TDDS 1. In studies involving removal and reapplication of transdermal matrix systems [8,9,17], the method developed for TDDS 2 can be adapted to estimate how long a person has to wear the patch. In addition, calculation of t eff is straightforward and does not involve the solution of a system of partial differential equations. ...
Article
Full-text available
The dynamic performances of two different controlled-release systems were analyzed. In a reservoir-type drug-delivery patch, the transdermal flux is influenced by the properties of the membrane. A constant thermodynamic drug activity is preserved in the donor compartment. Monolithic matrices are among the most inexpensive systems used to direct drug delivery. In these structures, the active pharmaceutical ingredients are encapsulated within a polymeric material. Despite the popularity of these two devices, to tailor the properties of the polymer and additives to specific transient behaviors can be challenging and time-consuming. The heuristic approaches often considered to select the vehicle formulation provide limited insight into key permeation mechanisms making it difficult to predict the device performance. In this contribution, a method to calculate the flux response time in a system consisting of a reservoir and a polymeric membrane was proposed and confirmed. Nearly 8.60 h passed before the metoprolol delivery rate reached ninety-eight percent of its final value. An expression was derived for the time it took to transport the active pharmaceutical ingredient out of the polymer. Ninety-eight percent of alpha-tocopherol acetate was released in 461.4 h following application to the skin. The effective time constant can be computed to help develop optimum design strategies.
... Increasing the application period and/or reducing the removal period would produce a more continuous delivery [21] and, therefore, a relatively constant plasma drug concentration. Clinical and theoretical studies show no significant drop in b-estradiol plasma concentration after patch removal and reapplication [25,26]. A steady-state bestradiol plasma level was achieved following application of the first patch. ...
Article
The integral transform technique was implemented to solve a mathematical model developed for percutaneous drug absorption. The model included repeated application and removal of a patch from the skin. Fick's second law of diffusion was used to study the transport of a medicinal agent through the vehicle and subsequent penetration into the stratum corneum. Eigenmodes and eigenvalues were computed and introduced into an inversion formula to estimate the delivery rate and the amount of drug in the vehicle and the skin. A dynamic programming algorithm calculated the optimal doses necessary to achieve a desired transdermal flux. The analytical method predicted profiles that were in close agreement with published numerical solutions and provided an automated strategy to perform therapeutic drug monitoring and control.
Article
Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 μg/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean ± SEM, 1.25 ± 0.06 before and 1.22 ± 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 ± 0.09 before and 1.36 ± 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (>0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.
Article
Synopsis The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy. Pharmacodynamic Properties 17β-Estradiol is the predominant estrogen produced by the ovaries in premenopausal women. Administration of transdermal estradiol to postmenopausal women (in dosages of 0.05 to 0.2 mg/day) elevates plasma estradiol concentrations into the range observed in premenopausal women at the early to mid follicular stage. Plasma estrone concentrations are increased to a much lesser degree and a physiological plasma ratio of estradiol to estrone (approximately 1: 1) is thus produced. As a result of the increased plasma estradiol concentrations, plasma concentrations of follicle-stimulating hormone (FSH) and luteinising hormone (LH) are decreased and vaginal cytology is converted to a pattern resembling that found in premenopausal women, with improvement of the maturation and karyopyknotic indices. Bone resorption is inhibited, as evidenced by a reduction in the urinary ratios of calcium and hydroxyproline to creatinine, and an increase in bone mineral density has been achieved in patients receiving long term treatment. Transdermal estradiol has a less marked effect than oral estrogens on lipid and lipoprotein metabolism; the plasma lipid profile does not appear to be significantly altered by short term treatment, but some studies of ⩾ 6 months’ duration have reported potentially beneficial changes in various lipid and lipoprotein fractions. Pharmacokinetic Properties The estradiol transdermal therapeutic system is designed to deliver estradiol at a constant rate for up to 4 days. Currently, 3 sizes of delivery system are available, with nominal delivery rates of 0.025, 0.05 and 0.1 mg/24 hours. Following application of transdermal estradiol to intact skin, maximum plasma estradiol concentrations are attained in postmenopausal women within 2 to 8 hours. Steady-state plasma concentrations of estradiol are linearly proportional to the dose administered; mean levels of around 23, 40, 75 and 100 ng/L occur in women with pretreatment estradiol levels ⩽ 10 ng/L from administration of 0.025, 0.05, 0.1 and 0.2 mg/day, respectively. Plasma levels of estradiol during transdermal therapy and reduction in menopausal symptoms, plasma FSH concentrations and urinary excretion of calcium are closely related. Estradiol is mainly metabolised in the liver, the major metabolites being estrone and estriol and their conjugates, which are considerably less potent than estradiol. The bulk of the metabolites are excreted in the urine as glucuronides and sulphates, although some enterohepatic recirculation may occur. Within 24 hours of removal of transdermal delivery systems, plasma concentrations of estradiol and estrone, and urinary excretion of estradiol and estrone conjugates, return to pretreatment levels. The plasma elimination half-life of estradiol is approximately 1 hour irrespective of the route of administration and the metabolic plasma clearance rate is between 650 and 900 L/day/m2. Therapeutic Use The efficacy of transdermal estradiol as estrogen replacement therapy in peri- or postmenopausal women has been evaluated in noncomparative, placebo-controlled and comparative clinical trials. Dosages ranging from 0.025 to 0.2mg daily have been used. In studies of ⩾ 2 months duration, treatment has generally been cyclical (3 weeks on, 1 week off) and sequential progestagen therapy has usually been administered for 5 to 12 days per cycle to patients with an intact uterus, in order to minimise endometrial proliferation. Climacteric symptoms — hot flushes, sweating, sleep disturbance, vaginal discomfort, poor concentration and irritability — have been eliminated or significantly improved during transdermal estradiol replacement therapy. In comparative studies transdermal estradiol has demonstrated efficacy in the control of climacteric symptoms at least equivalent to those of oral estradiol preparations, ethinylestradiol and conjugated estrogens, and subcutaneous estradiol implants or estradiol/prasterone depot injections. Data from preliminary studies suggest that transdermal estradiol, usually with sequential progestagen, is also effective in other indications for which estrogen therapy is prescribed, such as contraception and as hormone replacement therapy in patients with premature ovarian failure or bilateral oophorectomy participating in fertility programmes. Although transdermal estradiol inhibits bone resorption, few data are currently available regarding its effect on the incidence of osteoporosis and fractures in treated menopausal women. Analysis of patient acceptability of the transdermal route for estrogen replacement in several studies indicated that > 70% of patients preferred transdermal estradiol over oral or injectable therapies. Adverse Effects A significant proportion of patients experience dermatological reactions to the transdermal delivery device. Although these mostly consist of transient erythema/itching at the site of application, which can be minimised by rotation of patch application sites, severe irritation leading to discontinuation of therapy occurs in about 2.5 to 7% of patients overall. Otherwise, transdermal estradiol therapy is generally well tolerated, the most common systemic adverse symptoms being typical estrogenic effects, such as breast tenderness and spotting/bleeding and general effects such as fatigue, abdominal bloating and nausea, which result in discontinuation of treatment in < 4% of patients. Estrogenic stimulation of the endometrium occurs with transdermal estradiol therapy and coadministration of a sequential progestagen (which may also produce a more acceptable bleeding pattern) is therefore recommended for patients with an intact uterus in order to minimise endometrial proliferation. Unlike oral estrogens, transdermal estradiol does not stimulate hepatic metabolism and consequently plasma concentrations of renin substrate, sex hormone-, thyroxine- and cortisol-binding globulins and clotting factors are not elevated. It has been suggested that transdermal estradiol might be associated with a lower incidence of adverse effects than oral estrogen replacement therapies because of the lower circulating estrogen concentrations involved and the lack of untoward effects on liver metabolism. However, this has not been confirmed in comparative studies to date; generally, adverse effects have been comparable in patients receiving transdermal estradiol and those receiving oral or injectable estrogens. Dosage and Administration The recommended initial dosage of transdermal estradiol for the treatment of menopausal symptoms is 0.05mg daily, which may be increased in cases of inadequate response after 2 to 3 weeks’ treatment, or decreased if breast discomfort or breakthrough bleeding occur. For maintenance therapy the lowest effective dose should be used. Treatment may be continuous or may be given in 4-week cycles (3 weeks on/1 off). Sequential progestagen treatment should be administered for 10 to 12 days per month to patients with an intact uterus. The transdermal estradiol delivery system should be changed twice weekly. Contraindications to the use of estradiol include carcinoma of the breast or endometrium, leiomyoma of the uterus, endometriosis, vaginal bleeding of unknown origin, severe renal, hepatic, or cardiac disease and active or previous thromboembolic disease.
Article
Plasma luteinizing hormone, follicle-stimulating hormone, and estradiol were measured at 20-minute intervals for 24-hours in seven pubertal premenarchal girls whose sleep was monitored polygraphically. A circadian variation in plasma estradiol was demonstrated with the highest values occurring during the day (1400-1600 hours) and lowest values during sleep, a time when gonadotropin secretion was augmented.
Article
The bioavailability of estradiol from Oesclim® 50 and Systen® 50, two matrix-type estradiol transdermal systems with the same nominal delivery rate of 50 μg per 24 hours, was compared in a randomized, crossover pilot study of 12 healthy postmenopausal women. A 7-day washout separated the two 4-day application periods. Serum estradiol levels were determined by using radioimmunoassay before application of the transdermal system and at defined intervals thereafter. Higher serum estradiol levels were observed with Oesclim 50 than with Systen 50. Analysis of log-transformed, baseline-corrected pharmacokinetic values showed significant differences between the two transdermal systems. Except for the maximum serum concentration and concentration at 72 hours, all Oesclim 50 pharmacokinetic values were significantly higher than those of Systen 50 (P < 0.05). Estradiol bioavailability was approximately 1.5 to 2 times higher after application of Oesclim 50 than after application of Systen 50.
Article
Circulating plasma levels of 17β-estradiol after the administration of fixed dosages of 17β-estradiol show great variability depending upon product formulation, route of administration, and interindividual variation in absorption and metabolism. Two new 17β-estradiol transdermal delivery systems, Systen 50 (also called Evorel®) and Menorest®50 have recently been approved in Europe for the treatment of climacteric symptoms. Both transdermal systems deliver 17β-estradiol at a rate of 50 µg/day. The present study was undertaken to compare the plasma profiles of 17β-estradiol delivered by these 2 products in 30 healthy postmenopausal women according to a randomised, monocentric, single-blind, crossover protocol. Two 4-day patch application periods were separated by a 7-day washout period. Plasma 17β-estradiol concentrations were determined 24 hours and 30 minutes before and then 0, 2, 4, 8, 12, 24, 48, 60, 72, 84 and 96 hours after the first patch administration. 17β-Estradiol measurements were performed using a specific direct radioimmunoassay developed at the French Fondation de Recherche en Hormonologie laboratory. Bioequivalence was assessed by analysis of variance. The results demonstrated that the 2 products were similar in terms of maximum plasma concentration; however, mean concentration, concentration at 96 hours and area under the concentration-time curve were significantly (p < 0.05) greater with Menorest®50. Furthermore, 17β-estradiol concentrations decreased more rapidly with Systen®50 than with Menorest®50. These differences in the plasma profiles of 2 transdermal systems both delivering 50 µg/day of 17β-estradiol may have important clinical consequences both in terms of tolerance and effectiveness.
Article
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.
Article
The objective of this study was to evaluate the pharmacokinetics of estradiol and estrone, at steady-state, after repeated applications of Menorest® delivering 0.025, 0.050 and 0.100mg estradiol daily, and to determine the plasma concentration/administered dose relationship. It was an open randomised crossover study, with 3 treatment periods of 10.5 days separated by two 12-day intervening washout periods. Randomisation was conducted according to a latin square design. The clinical part of the study was carried out at CAP (Centre d’Activité Pharmacologique), Montpellier, and plasma estradiol and estrone concentrations were determined at CEPHAC (Centre d’Etudes et de Recherche en Pharmacie Clinique), St Benoit, France. The study included 30 healthy postmenopausal women, volunteers aged between 42 and 70 years (mean 59.13 ± 6.90 years). Each transdermal system dosage was applied for 3 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 dosage at regular intervals over 106 hours. Cutaneous tolerance was assessed after each transdermal system removal. After the third application of patches releasing 0.025, 0.050 and 0.100 mg/day, a linear relationship was established between the administered dose and the estradiol pharmacokinetic parameters [area under the plasma concentration-time curve from time 0 to 84 hours (AUC0–84h), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin) and average plasma concentration (Cav)]. This relationship did not exist between plasma estrone concentrations and estradiol administered doses, although these concentrations increased with the increased dosage. Adverse events were neither serious nor unexpected; none required discontinuation of the treatment, and their incidence was higher with the highest doses. Erythema and skin wrinkling were the most frequent cutaneous reactions — their frequency (related to the number of applications) was increased from 26 to 44% for erythema and from 2 to 40% for skin wrinkling when the administered dose increased from 0.025 to 0.100 mg/day. It was concluded that the linear relationship established between plasma estradiol concentrations and administered doses constitutes the basis for the dosage adjustment to the individual needs of postmenopausal women in the range 0.025 to 0.100 mg/day, and allows adjustment of the dose to deliver the minimum effective level of estrogen.
Article
The successful introduction of nitroglycerin transdermal delivery systems for the prophylactic treatment of angina pectoris has spawned an explosion of interest in this route of drug delivery in the field of pharmaceutics. Since that time, we have gained a great deal more knowledge concerning the design of membrane controlled delivery systems. This route of administration has been proposed and investigated in a number of disease states using several drugs. We would like to report our experience in investigating the transdermal route for long term treatment of postmenopausal symptoms using estradiol replacement therapy.The rationale for the development of a transdermal estradiol system is associated with the metabolic and pharmacological effects of orally administered estrogen replacement in post-menopausal women. Because estradiol is metabolized almost completely on first pass through the liver, orally administered estrogens result in nonphysiologic levels of the estrogenic metabolites of the natural ovarian hormone. Transdermal delivery of estradiol successfully by-passes the first pass effect and results in a more normal estrogen blood profile. The results of several biopharmaceutics studies demonstrate the characteristics of the membrane controlled delivery system which was designed around pharmacologic principles. In addition, a number of clinical trials have shown that total required doses of estradiol provided transdermally are only a fraction of those required by the oral route. We will also discuss problems associated with adequately defining total drug input from transdermal devices when working in these very small dosing ranges.
Article
Plasma luteinizing hormone, follicle-stimulating hormone, and estradiol were measured at 20-minute intervals for 24-hours in seven pubertal premenarchal girls whose sleep was monitored polygraphically. A circadian variation in plasma estradiol was demonstrated with the highest values occurring during the day (1400-1600 hours) and lowest values during sleep, a time when gonadotropin secretion was augmented.
Article
Women's views on the menopause and hormone replacement therapy were explored using a questionnaire given to women attending one general practice who were having hormone replacement therapy under the supervision of their doctor. Sixty four women (67%) responded. Although only 5% of women had requested hormone replacement therapy from their general practitioner the majority of women indicated that they had been helped by hormone replacement therapy. Eight per cent of women were using hormone replacement therapy primarily to treat menopausal symptoms with only 6% of women using it primarily as prophylaxis against osteoporosis. Many women were correctly informed about the effects of hormone replacement therapy but mistaken beliefs about its side effects may indicate the need for further health education. The desire for further information was striking: 59% of women wanted further information about hormone replacement therapy, and 80% of women would have liked to have had more information about the menopause before its onset. The media appeared to be an important source of information about health matters: 61% of women obtained information about hormone replacement therapy from either the television, magazines or newspapers. The role of the media and health workers in health education is discussed.
Article
Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However, oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects, 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy, Arnhem, The Netherlands), 100 μg/day for 4 weeks, and after 1 month without therapy, with oral estradiol (Progynova; Schering, Weesp, The Netherlands), 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary, the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean ± SEM, 1.25 ± 0.06 before and 1.22 ± 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 ± 0.09 before and 1.36 ± 0.09 during oral treatment). However, the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (>0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index, a decrease in relative percentage chenodeoxycholic acid in bile, and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary, oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.
Article
The estradiol transdermal therapeutic system is a cutaneous delivery device which delivers estradiol into the systemic circulation via the stratum corneum at a constant rate for up to 4 days. Physiological levels of estradiol (the major estrogen secreted by the ovaries in premenopausal women) can therefore be maintained in postmenopausal women with low daily doses because first-pass hepatic metabolism is avoided. In short term clinical studies, the beneficial effects of transdermal estradiol on plasma gonadotrophins, maturation of the vaginal epithelium, metabolic parameters of bone resorption and menopausal symptoms (hot flushes, sleep disturbance, genitourinary discomfort and mood alteration) appear to be comparable to those of oral and subcutaneous estrogens, while the undesirable effects of oral estrogens on hepatic metabolism are avoided. As with oral or injectable estrogen replacement therapy, concomitant sequential progestagen is recommended for patients with an intact uterus during transdermal estradiol administration, in order to reduce endometrial stimulation. Transdermal estradiol has been well tolerated in clinical trials, with local irritation at the site of application being the most common adverse effect. The incidence of systemic estrogenic effects appears to be comparable to that observed with oral therapy. Thus, transdermal estradiol offers near-physiological estrogen replacement in postmenopausal women in a convenient low-dose form which may avoid some of the complications of higher dose oral therapy. Long term epidemiological studies are warranted to determine whether transdermal estradiol therapy provides protection against osteoporosis and fractures and cardiovascular disease equivalent to that offered by oral and injectable estrogens. However, despite the importance of such data, it seems reasonable to conclude at this stage of its development that transdermal estradiol represents an important advance in hormone replacement therapy.
Article
The pharmacokinetic properties and biotransformation of two orally active oestrogens, piperazine oestrone sulphate (PE1S, 2.5 mg/day) and oestradiol valerate (E2V, 2.0 mg/day), given alone or in combination with levonorgestrel (LNG, 250 micrograms/day) were compared in 8 post-menopausal women, using a randomized cross-over design. The end points measured in peripheral plasma included oestrone (E1), oestradiol (E2), oestriol (E3), oestrone sulphate (E1S), oestradiol sulphate (E2S) and oestriol sulphate (E3S). In addition, LNG and sex-hormone-binding globulin SHBG concentrations were also assessed. The plasma levels of E3 were invariably below the detection limit (220 pmol/l). The levels of all the other oestrogens analyzed were consistently higher and the area under the curve significantly greater (except in the case of E3S) following PE1S administration than those recorded after E2V ingestion. The terminal half-lives of the circulating oestrogens measured after PE1S administration did not differ from those found after E2V administration. After 21 days of PE1S administration (in combination with LNG for the last 10 days), the maximum levels of all the oestrogens (except those of E2) were significantly higher than those seen after the first dose. No such difference was observed after E2V administration. There was no difference between the effects of the two treatment regimens with regard to the E1/E2 ratios, but the E1/E1S ratios were significantly lower after PE1S treatment than after E2V administration. It is concluded that, compared with an equivalent dose of PE1S, daily repeated oral administration of E2V yields consistently lower peripheral plasma levels of E2 and its principal metabolites. However, in contrast to PE1S therapy, prolonged administration of E2V does not result in an accumulation of the circulating oestrogens measured.
Article
There are large inter- and intra-individual variations in the serum concentrations of natural and synthetic sex steroids irrespective of the route of administration. Oral ingestion of steroids has a stronger effect on hepatic metabolism than parenteral administration, as the local concentration in liver sinusoids are 4-5 times higher during the first liver passage. Oestradiol and oestrone are interconvertible, dependent on the local concentrations in liver and target organs, and oestrone sulphate serves as a large reservoir. The oestrone/oestradiol ratio has no physiological significance, as oestrone is only a weak oestrogen. Oestrone is both a precursor and a metabolite of oestradiol. Oestriol is extensively conjugated after oral administration. Therefore, the oestriol serum levels are similar after oral intake of 10 mg and after vaginal application of 0.5 mg oestriol resulting in similar systemic effectiveness. Conjugated oestrogens can easily enter the hepatocytes but are hormonally active only after hydrolyzation into the parent steroids. Ethinylestradiol which exerts strong effects on hepatic metabolism and inhibits metabolizing enzymes, should not be used for hormone replacement therapy. Among the progestogens, the progesterone derivatives have less effects on liver metabolism than the norethisterone derivatives (13-methyl-gonanes and 13-ethyl-gonanes). The highly potent 13-ethyl-gonanes are effective at very low doses, because of a slow inactivation and elimination rate due to the ethinyl group.
Article
The statistical test of hypothesis of no difference between the average bioavailabilities of two drug formulations, usually supplemented by an assessment of what the power of the statistical test would have been if the true averages had been inequivalent, continues to be used in the statistical analysis of bioavailability/bioequivalence studies. In the present article, this Power Approach (which in practice usually consists of testing the hypothesis of no difference at level 0.05 and requiring an estimated power of 0.80) is compared to another statistical approach, the Two One-Sided Tests Procedure, which leads to the same conclusion as the approach proposed by Westlake based on the usual (shortest) 1-2 alpha confidence interval for the true average difference. It is found that for the specific choice of alpha = 0.05 as the nominal level of the one-sided tests, the two one-sided tests procedure has uniformly superior properties to the power approach in most cases. The only cases where the power approach has superior properties when the true averages are equivalent correspond to cases where the chance of concluding equivalence with the power approach when the true averages are not equivalent exceeds 0.05. With appropriate choice of the nominal level of significance of the one-sided tests, the two one-sided tests procedure always has uniformly superior properties to the power approach. The two one-sided tests procedure is compared to the procedure proposed by Hauck and Anderson.
Article
To determine whether the nonoral administration of estradiol (E2) might provide physiologic replacement without alteration of hepatic function, 20 postmenopausal women were studied before and after 3 weeks of treatment with either E2-containing transdermal therapeutic systems or placebo. Twenty premenopausal women were also studied. With E2-containing systems, serum E2 and estrone levels were restored to the premenopausal range. Variable responses of the different biochemical and biologic markers of the actions of E2 were observed. The most sensitive marker was vaginal cytology, with the E2 dosage reverting the maturation index to premenopausal values. Hot flashes, measured objectively, were reduced in frequency but not abolished. Serum levels of follicle-stimulating hormone and luteinizing hormone were lowered but remained higher than the premenopausal range. No significant changes were noted in urinary calcium/creatinine and hydroxyproline/creatinine ratios, which were used as markers of bone resorption. With active systems, no significant changes were noted in the concentrations of the hepatic proteins renin substrate and thyroxine-binding globulin or in the binding capacities of cortisol-binding globulin and sex hormone-binding globulin. These results indicate that transdermal E2 administration may be used to provide estrogen replacement while exerting limited effects on hepatic function.
Article
After physiological or surgical menopause, women are suddenly deficient in their main estrogenic hormone, 17 beta-estradiol. Only a very small amount of estradiol is still produced from adrenal precursors. More than 50 per cent of all postmenopausal women suffer for varying periods of time from the symptoms of this estrogen deficiency, most notably vasomotor instability (hot flashes) and sleep disturbances. The trophic symptoms of estrogen deficiency have longer lasting and cumulative consequences: accelerated loss of bone density that eventually increases the risk of fractures, genitourinary atrophy resulting in dyspareunia and urinary atrophy; and lipoprotein changes with increased risk of coronary heart morbidity and mortality. Today estrogen deficiency is mainly treated by oral estrogens--either conjugated equine estrogens or estradiol--in milligram doses far in excess of what would be required by the parenteral route. Taken orally, estradiol is largely transformed to estrone through metabolism in the liver. Certain undesirable side effects of estrogen therapy (e.g., increased renin substrate) are caused by the unphysiologic nature of the oral route of administration. Dosage forms for parenteral estrogen administration have been widely studied: vaginal or percutaneous creams, intranasal solutions, and sublingual tablets. All of these result in a pronounced, transient elevation of plasma concentrations of estradiol and a minor increase of estrone. An improved regimen, which produces more constant plasma concentrations, is achieved with an experimental estradiol implant or with a vaginal ring delivering estradiol. These studies demonstrate that daily estradiol doses of 0.2 mg and less are effective in reducing hot flashes. Effective doses of conjugated estrogens and estradiol administered by different routes achieve estradiol plasma concentrations of similar magnitude (between 35 and 100 pg/ml). Estrone plasma levels vary widely with these different regimens and do not seem to be directly related to efficacy. In summary, the literature indicates that efficacy of estrogen replacement for the treatment of the menopausal symptoms appears to relate to the magnitude of estradiol plasma levels; effective therapy is achieved by an estradiol regimen that maintains plasma estradiol levels of at least 35-55 pg/ml. Efficacy of estrogens in the prevention of osteoporosis as assessed by densitometry has been demonstrated for conjugated oral estrogens.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
A novel patch containing 17 beta-Estradiol exhibits improved kinetic profiles compared to the currently available leading transdermal product. The blood concentrations produced by the newly developed matrix patch are stable over 3 to 4 days, thus avoiding the occurrence of 17 beta-Estradiol peaks in the blood. In an additional clinical study an almost linear relationship could be identified between the patch size (Test patch: 7.25, 14.5 and 29.0 cm2) and the obtained 17-estradiol bioavailability (judged on AUC, cmax, c(ave), Cmin). These results are corroborated by the additional in vitro experiments. An almost constant drug delivery rate of 48 micrograms +/- 15 micrograms/day of 17 beta-Estradiol per 13.85 cm2 patch over 4 days can be detected through excised human skin. No statistically significantly different transdermal flux rates of 17 beta-Estradiol were detected in 3 different batches of the transdermal drug delivery system in vitro. Statistical evaluations were performed with the 3-Way-Anova test on the 0.05 significance level. This newly developed product presents a kinetically optimized transdermal 17 beta-estradiol patch for hormone substitution therapy.
Article
Postmenopausal hot flashes are characterized by sweating and peripheral vasodilation and occur more frequently during increased heat loads. The circadian rhythm of core body temperature (TC) is well known and suggests that hot flashes will be most frequent when core temperature is highest. This hypothesis has not been tested previously. Ten symptomatic and six asymptomatic postmenopausal women were recruited from advertisements and screened. Each received 24-h ambulatory monitoring of sternal skin conductance levels to detect hot flashes, ambient temperature, skin temperature, and TC. The last measure was recorded using an ingested radiotelemetry pill. Cosinor analysis demonstrated a circadian rhythm (P < 0.02) of hot flashes with a peak at about 1825 h. TC values of the symptomatic women were lower than those of the asymptomatic women (P < .05) from 0000-0400 h and at 1500 and 2200 h. The majority of hot flashes were preceded by elevations in TC. Thus, elevated TC may serve as one trigger of menopausal hot flashes.
Article
The purpose of this study was to evaluate the role of the opioid system and the estrogen environment in the nocturnal secretion of melatonin in women with secondary amenorrhea (SA). Nocturnal melatonin concentrations in patients with SA were significantly higher than in normal women (p < 0.01 vs. women with normal menstrual cycles). There were significant negative correlations between cumulative melatonin levels (between 8 p.m. and 8 a.m.) and serum estradiol-17 beta (r = -0.561, p < 0.01) and between peak serum melatonin values and serum estradiol-17 beta concentrations (r = -0.608, p < 0.01) in SA. Intravenous administration of a conjugated estrogen (Premarin 20 mg) significantly suppressed nocturnal melatonin secretion (p < 0.05), but a continuous intravenous infusion of naloxone (1.6 mg/h from 8 p.m. to 6 a.m.), an opiate antagonist, did not affect nocturnal melatonin secretion in SA. Our findings suggest that elevated nocturnal melatonin secretion may be related to low estrogen levels, but that it is not mediated by the opioid system.
Article
Although estrogen replacement therapy (ERT) has proven highly effective in preventing both the short- and long-term adverse clinical outcomes associated with menopause, it is important to recognize that the pharmacokinetic and metabolic effects of ERT vary with dosage and route of delivery. One of the most promising methods of administering ERT is the transdermal therapeutic system (TTS), or "patch," the efficacy of which is comparable to that of other forms of ERT, but whose unique pharmacokinetic profile may confer several distinct clinical advantages over the oral route. The present article addresses some of the key pharmacokinetic and metabolic differences between these two dosing forms, with particular emphasis on their respective effects on gonadotropins, hemostasis and coagulation, lipid metabolism, hepatobiliary function, and bone. An extensive review of clinical experience accrued over the past decade suggests that transdermal ERT is a viable alternative to oral ERT.
Article
The bioavailability of estradiol (CAS 50-28-2; E2) from a new "matrix type" estradiol transdermal patch (Dermestril; Test patch) was compared to that of the widely used "liquid-reservoir, membrane-controlled type" transdermal patch (Reference patch) in a two-way randomized cross-over study on 28 healthy postmenopausal women, during a single 4-day application of 2 patches (total content 8 mg E2, total nominal release rate 100 micrograms E2 in 24 h). Evaluated from the AUC0-96h, the extent of bioavailability was practically the same for the two patch types. Conversely the rate of bioavailability was significantly different, because from the Reference patch the release rate is fast in the first 24 h, leading to an E2 peak at 8 h and to a Cmax in average at 23 h. But after the 2nd day the release/absorption rate declines markedly, leading to E2 serum concentrations at the 3rd and 4th days possibly below the effective threshold. From the Test patch the release/absorption rate of E2 is more constant, leading to sustained E2 concentrations during the 4 days of application, with smaller fluctuations than during application of the Reference patch. In conclusion the Test patch can be considered practically bioequivalent to the Reference patch with regard to the extent of absorption, but not with regard to the rate of absorption, because the E2 concentrations in serum are more constant during the application of the Test transdermal patch than during the application of the Reference.
Article
Objective: Bioavailability of estradiol delivered from a newly developed matrix-type transdermal therapeutic system (MTTS) was compared with that of the conventional reservoir-type system (RTTS). Both formulations have a nominal delivery rate of 50 μg per day of 17β-estradiol (E2). Plasma concentrations of E2 and estrone (E1) were determined at steady state during a 96-h application of each formulation to 34 postmenopausal volunteers, using a two-stage randomized two-period crossover design. Results: The MTTS proved to be equivalent to the RTTS with respect to the extent of E2 absorption. Due to differences in patch design and composition, the rate of absorption was different between the two systems, with less fluctuating E2 plasma levels during application of the matrix system. Local tolerability and adhesion of MTTS appeared to be better than those of the reservoir system.
Article
The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17 beta-estradiol (CAS 50-28-2, E2) after the application of two types of matrix patches for the transdermal delivery of E2: MenorestTM (the test patch) with delivery rates of 37.5, 50 and 75 micrograms E2/day and a reference patch with a delivery rate of 50 micrograms E2/day. All 3 test patches were identical in composition, achieving different transdermal E2 delivery rates by variations in the surface area (11.0, 14.5 and 22.5 cm2). All 4 patches were each worn by 24 postmenopausal women over a 4-day period (i.e. 96 h), each of the 4 treatment periods being separated by a 7-day wash-out period according to a randomized, 4-way crossover design. Blood samples were collected before and 3, 6, 9, 12, 24, 34, 48, 58, 72, 84, and 96 h after each patch application. Plasma E2 concentrations were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h; Cmax, tmax, Cmin, Caverage. The course of the E2 plasma levels over the total test period (96 h) was relatively constant for all patches. For the test patch, a linear relationship between the pharmacokinetic parameters and the different patch areas (i.e. dosages of 37.5, 50, 75 micrograms E2/d) could be shown (correlation coefficient 0.99). The resulting Cmax values for the patch were: 44.2, 58.3, and 92.1 pg E2/ml, corresponding to Caverage values of 39.5, 45.5, and 70.6 pg E2/ml. The reference patch and the test patch, at a dose of 50 micrograms E2/d, were similar in terms of Cmax, while the Caverage, AUC0-96h and Cmin were significantly higher with the test patch. The systemic bioavailability of the reference patch was comparable to that of the test patch at a dose of 37.5 micrograms E2/d: AUC0-->96h 3017.5 +/- 1312.4 pg/ml.h for the reference patch and 3375.9 +/- 1254.7 pg/ml.h for the test patch. A physical model for the calculation of the course of the E2 levels was used to describe the experimentally determined data. However, in the evening, periodically higher E2 plasma levels were observed for all patches than in the morning. From these results it can be concluded that E2 plasma profiles produced by the test patch are reproducible, and in the physiological range consistent with the early to mid follicular level in the premenopausal woman over 4 days (96 h), correlating with the doses administered (37.5-50-75 micrograms E2/d). Additionally, the systemic bioavailability of the test patch at a dose of 37.5 micrograms E2/d is comparable to that of the reference patch at a dose of 50 micrograms E2/d.
Article
In order to compare the pharmacokinetics of two transdermal estrogen replacement therapy (ERT) systems designed to release 50 micrograms 17 beta-estradiol/day, two studies were performed in healthy postmenopausal volunteers. Both studies had a cross-over design and incorporated a 1-week wash-out period between treatments. In the first study, Menorest 50 and Systen 50 (Evorel 50) were compared over four days of application in 30 women. In the second, 13 women wore each of the two systems for a total of 12 days each (three patches each for 4 days), and comparison was made during the third patch period (steady state, between days 8 and 12). Plasma 17 beta-estradiol levels were assayed using specific direct radioimmunoassays, and pharmacokinetic parameters were calculated by standard methods. All the samples of the first study were re-analysed using a different radioimmunoassay and the results of both assays were compared. In both studies, plasma 17 beta-estradiol levels rose at a comparable rate and reached similar peak levels with each of the two formulations. Levels then remained relatively constant throughout both evaluation periods with Menorest 50, but began to decline after 12 hours in the first study and after 30 h under steady state conditions in the second study with Systen 50. The difference between the two products was statistically significant in both studies. Analysis of pharmacokinetic parameters confirmed the greater bioavailability of Menorest 50. In addition, 17 beta-estradiol levels remained within the suggested therapeutic ranges for relief of acute symptoms and protection against osteoporosis for longer periods of time with Menorest 50 than with Systen 50. Since the acute efficacy, long-term protective effects, side effects and risks associated with ERT may depend on critical threshold plasma levels, much attention should be paid to the pharmacokinetic profiles of different formulations. The comparison of these two different radioimmunoassays demonstrates the comparability of their results.
Article
Although circadian rhythms have been described for many human functions, there are minimal data on circadian rhythms related to skin physiology. This study investigated the circadian rhythmicity of skin variables related to skin barrier function in humans. We measured transepidermal water loss, stratum corneum moisture, skin surface pH, and skin temperature in 16 healthy volunteers (nine men and seven women, aged 23-53 y). Subjects were sampled every 2 h in two sessions over a 24 h span. Twelve samples were obtained for each variable in the following sites: forehead, forearm, upper back, and shin. We used cosinor analysis and ANOVA to validate observed differences. Time-dependent rhythms were detected in most skin variables except in stratum corneum hydration. We found a statistically significant circadian rhythmicity characterized by cosinor analysis in transepidermal water loss, skin surface pH, and skin temperature on the forearm, forehead, and shin. Peak-trough differences occurred in all locations. The values of the same variables measured at different sites correlated positively, whereas the values of the different variables did not. These results suggest that skin permeability is higher in the evening and night than in the morning. These data may be clinically relevant in several aspects applied to skin physiology and topical drug application.
Article
The aim of this study was to investigate the systemic bioavailability and plasma profiles of 17beta-estradiol (E2) after the application of three matrix patches for the transdermal delivery of E2: Menorest, Tradelia, and Estraderm MX claiming to deliver a dosage of 50 microg E2/day. All three patches were each worn randomly by 21 postmenopausal women volunteers over a 4-day period (i.e. 96 h). Each of the three treatment periods were separated by an at least 7 day wash out period according to a randomized, 3-way crossover design. Blood samples were taken from the antecubital vein before and 3, 6, 9, 12, 24, 28, 33, 48, 57, 72, 81, and 96 h after application. E2 plasma values were determined by a specific direct radioimmunoassay method. The following pharmacokinetic parameters were evaluated: AUC0-96h, Cmax, Tmax, Cmin, C(average). The time to reach the maximal E2 value of 32 h was the only pharmacokinetic parameter which was identical for all three patches. Menorest produced the highest E2 bioavailability judged by the AUC0-96h = 3967.8 +/- 1651.8 pg/ml, C(average) = 41.3 +/- 21.3 pg/ml, Cmin = 36.8 +/- 8.6 pg/ml. Tradelia showed statistically not significantly smaller C(average) = 38.9 +/- 17.0 pg/ml, AUC0-96h = 3737.9 +/- 1637.6 pg/ml x per h, and Cmin = 33.8 +/- 26.7 than Menorest. Estraderm MX showed lowest E2 plasma profiles Cmax = 38.9 +/- 25.1 pg/ml, C(average) = 33.2 +/- 17.1 pg/ml, AUC0-96 = 3192.1 +/- 1646.0 pg/ml per x h. Menorest showed the smallest fluctuation over the entire test period, similar to Estraderm MX, while Tradelia showed the highest E2-fluctuation (P < 0.01): Tradelia exhibited the highest Cmax = 48.0 +/- 20.3 pg/ml. When E2 baseline levels, prior to patch application are subtracted individually from the produced E2 plasma level, Estraderm MX is not bioequivalent to Menorest (P < 0.05). A circadian curve pattern of the E2 plasma level was observed for all patches: in the evening higher E2 plasma level were always detected compared with the morning, however, less pronounced with Estraderm MX. Individual comparison of AUC0-96h of each patch exhibited a large interindividual variability of 2000-8000 pg/ml per h for all three patches but relatively small individual variability: women with high E2 bioavailability (high responders) maintained high bioavailability in all applied patches, women identified as low and medium responders remained the same regardless of the applied patch. Menorest produced in 2/3 of all postmenopausal women with the highest E2 bioavailability (AUC0-96h), Tradelia was found in less than 1/3 (28.6%), and Estraderm MX in only one postmenopausal woman. Menorest only produced the highest reduction in postmenopausal symptoms together with Tradelia. Estraderm MX produced a smaller reduction in postmenopausal symptoms compared to Menorest and Tradelia. The observed side-effects were approximately equal in all three patches, with a maximum value after 72 h. It can be concluded that the three patches for the transdermal delivery of E2 claiming to deliver 50 microg E2/day differed from each other in their pharmacokinetic performance, although statistically not significant: Menorest exhibited the highest C(average), AUC and Cmin, and the lowest fluctuation, followed by Tradelia and Estraderm MX.
Article
To compare two estradiol transdermal matrix systems with regard to bioavailability, pharmacokinetics and tolerability. A single centre, open, randomized, comparative cross-over study in 20 healthy postmenopausal women. Menorest with 3 or 4 days of suggested use and Climara with 7 days of suggested use (both 50 microg/24 h) were compared at steady state. Two 14-day treatment periods were separated by a 4 week washout. Plasma levels of estradiol were monitored during the second week of each treatment. Tolerability was assessed by open questions and inspection of the application site. There were no differences between the two treatments with regards to AUC, Cmax, Cmin, Caverage or fluctuations of plasma estradiol. Tmax was significantly shorter for Menorest than Climara. Cmax and Cmin were significantly higher for the second Menorest patch during the monitoring period compared to the first. All local reactions were mild and there were three cases of erythema with Menorest and a total of 21 skin reactions in 15 subjects with Climara. Systemic tolerability was similar between treatments with eight estrogen-related adverse events in eight subjects (period pains, uterine bleeding, mastodynia, headache and vaginal discharge) with Menorest and 13 events in ten subjects with Climara. The bioavailability of estradiol from the two matrix transdermal delivery systems Menorest and Climara was similar, but the products were not bioequivalent because Tmax was significantly shorter for Menorest than for Climara. Tolerability of treatment was good for both patches but with a higher number of local reactions and estrogen related adverse events for Climara.
Article
We compared the clinical efficacy and circulating estrogen levels from two transdermal delivery systems, 'drug-in-adhesive' type, in 20 healthy postmenopausal women. Both patches, developed by Beta Pharmaceutical Laboratories in Argentina, deliver estradiol at a rate of 50 micrograms/day; the replacement frequency of system A (TrialSat) was twice a week and for system B (TrialSat LA) once a week. The women were treated for 180 days, in a continuous regimen, with additional oral medroxyprogesterone acetate 5 mg/day for 14 days of each cycle. Blood samples were taken at the end of the wearing period: the 3rd day for Group A and the 7th day for Group B, to determine levels of estradiol, estrone, non-sex hormone binding globulin (SHBG)-bound estradiol and SHBG. Both treatments had similar clinical efficacy and were well tolerated. Plasma estradiol levels were higher in Group A throughout the study, probably owing to the different sampling times. SHBG and non-SHBG-bound estradiol were unchanged in both groups. As there was a similar performance of both delivery systems, the 7-day patch may be preferable, and produce greater compliance.
Clinical pharmacoki-netics-concepts and applications. Chicago: Lea and Febinger, pp. 206±246. 21. SAS Language: Reference, Version 6, First edition
  • Rowland M Tozer
  • Tn
Rowland M, Tozer TN. 1980. Clinical pharmacoki-netics-concepts and applications. Chicago: Lea and Febinger, pp. 206±246. 21. SAS Language: Reference, Version 6, First edition. 1990. Cary, NC: SAS Institute, Inc., pp. 309±389.
Library of diffusion models for Scientist TM . Experimental data ®tting with Laplace transforms
  • Micromath
  • Inc
MicroMath, Inc. Library of diffusion models for Scientist TM. Experimental data ®tting with Laplace transforms. 1990. Salt Lake City, UT: MicroMath Scienti®c Software.
Estrogen replacement therapy by transdermal estradiol administration
  • Laufer LR
  • de Fazio JL
  • Lu JKL
Kinetik eines neuen Pflasters zur transdermalen Applikation von 17β-Estradiol
  • Rohr UD
  • Nauert C
  • Ehrly AM
Statistische Methoden zum Nachweis von Äquivalenz
  • Wellek S
Principles of Competitive Protein Binding Assays
  • Yalow R
Circadian 17β‐Estradiol Rhythm and the importance for therapy
  • Rohr
24‐hour plasma profile of estradiol and testosterone in pubertal girls
  • Goji
There are no circadian estradiol plasma profiles in postmenopausal women
  • Lønning
Kinetik eines neuen Pflasters zur transdermalen Applikation von 17β‐Estradiol
  • Rohr
Introduction and general consideration
  • Yalow
A comparison of the two one sided test procedures and the power approach for assessing equivalence of average bioavailability
  • Schiurmann