Article

17β-Estradiol delivered by three different matrix patches 50 μg/day A three way cross-over study in 21 postmenopausal women

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Abstract

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.

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Objective: Postmenopausal women have higher risk of cardiovascular events compared with premenopausal. The aim of this clinical study was to evaluate the effect of hormone replacement therapy (HRT) on the atherogenic profile in apparently healthy postmenopausal women. Method: The subjects were 76 healthy postmenopausal women, aged 45 to 59 years, and 15 premenopausal women with regular cycles, aged 40 to 45 years. 63 postmenopausal women completed the study. None of the participating women had a history of hypertension, diabetes mellitus or medications known to affect the cardiovascular system. Twenty seven postmenopausal women received daily 50 micrograms of transdermal estradiol and 100 milligrams of oral progesterone. Thirty six dit not receive HRT. Checkups were preformed at baseline and after six months of treatment, except the group of premenopausal women (only at baseline). Examinations consisted in measurement of body weight, length, waist/hip ratio and plasma levels of biochemical parameters. Results: Estradiol levels were higher among premenopausal women than among treated and non-treated postmenopausal women (83′78.47 versus 10′3.99; 12′4.56 mg/l, p<0.0001). Levels of serum cholesterol (198′30.2 versus 236′33.7; 228′32.8 mg/dl; p<0.002), LDL-cholesterol (120′25 versus 151′34.2; 144′31.5 mg/dl, p<0.02), uric acid (3.98′0.5 versus 4.6′1; 4.8′1 mg/dl, p<0.004) and homocysteine (9.8′3.3 versus 13′3.1; 11′1.7 mmol/l, p<0.02) were higher among postmenopausal women than among premenopausal women. The treated women showed higher levels of serum estradiol (49′34.43 versus 10′3.99, p<0.0001) and CRP (0.11′0.06 vs. 0.24′0.12 mg/l, p<0.05), lower waist/hip ratio (0.82′0.06 versus 0.83′0.05, p<0.03), glucose (78′15.4 versus 85′14.3 mg/dl, p<0.03), cholesterol (215′33.2 versus 236′33.7 mg/dl, p<0.03), triglicerides (90′30.1 versus 106′47 mg/dl, p<0.003) and calcium (9.4′0.4 versus 9.5′0.4 mg/dl, p<0.0005) than postmenopausal women without hormone replacement. Conclusion: That HRT may have a favourable effect on atherogenic profile in apparently healthy postmenopausal women.
Article
Estrogen replacement therapy is effective in relieving typical postmenopausal symptoms; it prevents osteoporosis and reduces the risk of cardiovascular diseases. Various delivery forms and routes of administration of estradiol are currently available, but transdermal delivery is getting increasingly popular. It bypasses the hepatic first-pass metabolism, eliminates poor absorption during gastrointestinal disturbances, minimizes the potential of drug interactions and allows delivery of constant levels of hormones. Transdermal delivery systems (TDS) enable fast hormone release in blood circulation. There are two different TDS - the transdermal reservoir patch and matrix patch. The transdermal matrix system may be preferable because its use is associated with a lower incidence of side effects, more stabile plasma estrogen concentrations, delivery of consistent therapeutic serum levels of estradiol and better bioavailability. Results obtained by comparing several matrix systems show that different TDS with the same declared amount of hormones released in blood circulation do not have equal bioavailability and pharmacokinetic profile. Comparison is made of absorption and bioavailability of estradiol between TDS and different therapeutic forms, i.e. gel. Pharmacokinetic profiles of estradiol are different, but bioavailability and cmax do not differ significantly. There is a big difference in cmin (lower for TDS). Fluctuations in plasma concentrations are therefore higher for TDS. TDS is also used as a contraceptive. Dosing schedule is simple to follow, user-controlled, and easily reversed. Comparison is made between 3 contraceptive methods: combined oral contraceptive, TDS and vaginal ring. Individual serum levels with combined oral contraceptive showed the highest variability as a result of its dosing regimen and exposure to ethinylestradiol was the highest. Vaginal administration of hormones affords much lower, more stable and far more precise dosing than either the transdermal or oral routes.
Article
Former epidemiological studies have suggested a benefit of postmenopausal therapy in providing protection against cardiovascular disease and osteoporosis. Recent, prospective, randomised, controlled studies have found no such benefit against coronary disease and, in addition, point to a greater risk of breast cancer. Discrepancies between recent prospective trials and former observational studies, particularly regarding cardiovascular risks, could be related to the type of substances used and their dosage. The occurrence of breast cancer is increased with oestro-progestative association apparently regardless of the progestative used.
Chapter
Over the past few decades there have been many advances in our understanding of the physicochemical properties of both formulation systems and their ingredients. These have led to the ability to develop physically, chemically, and biologically stable products. There has also been a signi?cant increase in our knowledge of the properties of skin and the processes that control skin permeation. The ground rules for skin permeation were laid down by Scheuplein and Blank in the late 1960s and early 1970s (1), and these have been updated on a reasonably regular basis (2-8). We have learned, for example, that the permeation of compounds across intact skin is controlled fundamentally by the stratum corneum, and it is the chemical composition and morphology of this layer that usually determines the rate and extent of absorption (9,10). Similarly, we have discovered how to modify this barrier, by chemical or physical means and, thereby, alter the rate of diffusion of many permeating molecules (11,12).
Chapter
The transdermal delivery of drugs to the systemic circulation is an established route of drug administration for a variety of small molecules. Transdermal drug delivery is characterized by constant plasma profiles through zero-order drug release for up to several days, the circumvention of the first-pass metabolism as well as its noninvasive alternative to oral dosing. Several drugs have been developed for chronic or acute conditions affecting older adults like for example pain, M. Alzheimer and M. Parkinson. Transdermal drug delivery offers some key advantages for the treatment of older adults, but also requires special attention when prescribed to older patients taking into account the individual risk–benefit profile. This chapter is intended to provide a short overview on transdermal drug delivery with the focus on older patients and reviews the major transdermal drug delivery products.
Article
The objective of this study was to evaluate whether long-term usage of hormonal contraceptives modifies the steroid receptor expression in the human vaginal epithelium of healthy young women. In a cross-sectional study, three groups of hormonal contraceptive users [combined oral contraceptives (COCs), levonorgestrel implants (LNG) and depot medroxyprogesterone acetate injections (DMPAs)] were compared to controls. Fifteen subjects (20-34 years) were enrolled to each group. Vaginal biopsies were collected at two occasions from each subject, and serum concentrations of E(2) and progesterone were measured. Monoclonal antibodies directed against progesterone receptors (PRs) and estrogen receptors (ERs) were used in immunohistochemistry on formalin-fixed tissue sections of vaginal mucosa. A program for immunohistomorphometric quantification was devised to estimate frequency of epithelial steroid receptor-expressing cells. Progesterone receptor expression was markedly down-regulated and significantly reduced in DMPA users compared to controls, COC and LNG users. In DMPA users, the ER expression was significantly elevated in the first compared to the second sample, and significantly elevated compared to LNG users. Estradiol concentration in serum was significantly reduced in hormonal contraceptive users compared to controls. Steroid receptor expression in human vaginal epithelium is altered by long-term use of DMPA compared to controls.
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
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
Purpose. The aim of our study was to investigate the high fluctuations of Estradiol (E2) plasma levels transdermally delivered in postmenopausal women by a commercially available membrane controlled reservoir system (MCRS). Methods. The transdermal E2 flux either out of a complete MCRS or across its membrane out of defined ethanol water mixtures was determined, as well as E2 plasma profiles in 6 postmenopausal women produced by a MCRS. Results. The transdermal in vitro E2 flux rate out of a complete MCRS, claimed to deliver 25 g/day, increased steadily, reaching a maximum value of 2.06 0.58 (g/h at 30 to 40 hours and decreased to a rate of about 0.5 (g/h from 60 to 90 hours. No statistically significant differences between plasma profiles calculated from the in vitro investigation and derived from a clinical study could be identified. The E2 flux in defined ethanol/water mixtures across MCRS-membrane, adhesive and skin layer increased with increasing ethanol concentrations up to a maximum of 227 34 ng/cm2/h at an ethanol concentration of 62.5% (V/V) and decreased with further increase in the volume fraction of ethanol. Conclusions. In vitro as well as in vivo investigations showed high fluctuation of E2 plasma profiles in postmenopausal women produced by the MCRS. These fluctuations are caused by a non-constant input rate of E2 which may be due to changing ethanol concentrations in the reservoir of the MCRS.
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
In this study of 13 hypogonadal men (25-69 years of age), three open-label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration-time curve from 0 to 27 hours (AUC0-27) values for testosterone after one-day applications to the upper buttocks, upper arm, and back were 9,560 ng.hr/dL, 8,651 ng.hr/dL, and 8,988 ng.hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days.
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.
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
To determine whether there is a dose-response effect of percutaneous oestradiol implants on the skeletons of postmenopausal women using a range of doses available in clinical practice. One year randomised study. Forty-five postmenopausal women who requested oestrogen replacement therapy were randomised to receive 25 mg, 50 mg, or 75 mg oestradiol implants. The bone mineral density changes were compared with a control group of 15 untreated women. Dual energy X-ray absorptiometry using Hologic 1000 QDR before treatment and after one year of treatment. Plasma oestradiol and follicle stimulating hormone levels before treatment and after one year. There were significant correlations between the plasma oestradiol levels and the percentage increase in bone density at the lumbar spine, the total hip, the femoral neck, and the trochanter. The median (range) plasma oestradiol level was 327 pmol/l (114-853) in the 25 mg group, 358 pmol/l (220-957) in the 50 mg group and 518 pmol/l (167-828) in the 75 mg group. Three women who lost a significant amount of bone from the clinically relevant sites in the 25 mg oestradiol group all had plasma oestradiol levels below 300 pmol/l. None of the women in either the 50 mg or 75 mg oestradiol groups lost bone from these sites. Oestradiol implants resulted in a wide range of circulating oestradiol levels with each of the doses used. There was a significant relation between plasma oestradiol levels and the increases in bone density at both the lumbar spine and the proximal femur. None of the women lost bone density at the clinically important sites of the spine and femoral neck if their plasma oestradiol levels were above 300 pmol/l.
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.
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