CLINICAL PHARMACOKINETICS
Clin. Drug Jrwest, 10(3): 172-178. 1995
1173-2563/95/0009-0172 / S0350/0
© Adis Internationa l limit ed . All rights reserved
Bioavailability Study of Menorest®, a New Estrogen Transdermal Delivery System, Compared with a Transdermal Reservoir System Y. Le ROUX,l M.L. Borg,l M. Sibille,2 J. Thebault,3 A. Renoux,3 M.J. Douin,3 F Djebbarl and M.P Dain 1 1 Rhone-Poulenc Rorer, Antony, France 2 Association de Recherche TMrapeutique, Lyon, France 3 Institut Aster, Paris, France
Summary
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 membranelreservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomi sed, crossover study, with 2 treatment periods of 10.5 days separated by a IO-day washout period and with a I-week follow-up . Participants were studied at Institut Aster, Paris, and Association de Recherche Therapeutique (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 (AVC) 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 Cay 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.
Bioavailability of Menorest®
Estrogen replacement therapy (ERT) is widely recognised as being effective in relieving postmenopausal vasomotor symptoms such as hot flushes and night sweats, minimising atrophic vaginal changes,[1-3] preventing osteoporosis[4-6] and reducing the risk of cardiovascular diseases[7-1O] that occur after the exhaustion of ovarian estrogen secretion at menopause. The optimal form of ERT would have to increase 17~-estradiol (E2) plasma levels into the range observed in premenopausal women at the early or mid-follicular stage,[II] with a physiological plasma ratio of estradiol (E2) to estrone (El) of approximately 1: 1 (estradiol being the predominant estrogen produced by the ovaries). Estradiol should be delivered in a sustained manner and the amount provided should be sufficient to alleviate vasomotor symptoms, reverse atrophic vaginal changes, prevent osteoporosis, and provide cardioprotection,[12] with minimal adverse effects. Various forms of ERT are currently available: oral, topical cream or gel, suppositories, implants and transdermal delivery systems. The oral route was the first and, to date, the most widely used form,[13] while transdermal forms have been more recently developed. Oral administration of estrogens can give rise to two types of problems. The oral route requires relatively high dosages of estrogens to compensate for the extensive hepatic first-pass effect. About 60 to 90% of orally administered estrogens are converted into estrone (E I) and inactive metabolites,[3,11,14] and estrone levels are much higher than those found in premenopausal women, resulting in a decreased ratio of estradiol to estrone. High concentrations of estrogens in the portal circulation enhance the hepatic synthesis of estrogensensitive proteins with increased plasma levels of renin substrate and several hormone-binding globulins, leading to undesirable consequences such as hypertriglyceridaernia[15-17] and gallbladder diseases.l 18-20] High doses of oral estrogens decrease the plasma concentration of the main coagulation inhibitor (antithrombin III) and increase plasma levels of several coagulation factors.l 21 -24] In addi© Adis International Lim~ed . All rights reserved.
173
tion, oral ERT results in marked fluctuations above and below the desired mean serum concentrations of estradiol. [3,25] Transdermal administration of estradiol (gel and transdermal systems), which avoids first-pass hepatic metabolism, prevents some of the unwanted effects of the oral route and reduces the dose of estrogen required to achieve the expected plasma levels. However, the first reservoir/membrane system required the addition of ethanol[ll] to increase the transdermal flow of estradiol levels, with an increased risk of cutaneous reactions. Estradiol gel needs frequent administration (once daily) and it is difficult to control the area of application of the active ingredient, resulting in variability of administered doses. Menorest® (Rhone-Poulenc Rorer, Antony, France, and Collegeville, Pennsylvania, USA) is a new trans dermal system in which estradiol is uniformly dispersed in a thin (0.33mm) and transparent adhesive matrix, without alcoholic solvent. The released daily dose is proportional to the surface area: Menorest® 50 is designed to deliver 50llg! 24h of estradiol from a surface of 14.5cm2 at a constant rate over the 3 to 4 days of suggested use. The current study was carried out to compare the bioavailability and pharmacokinetic profile of Menorest® and of the reservoir/membrane transdermal system (Estraderm® TTS) using the same nominal daily delivery (50 llg/day), and to evaluate the short term safety and skin tolerability of the two products. PartiCipants and Methods Participants
Thirty-one healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean age ± SO: 58.0 ± 4.1 years), participated in the study and were treated in two clinical units: Institut Aster, Cognacq-Jay Hospital, Paris, and Association de Recherche Therapeutique (ART), Lyon, France. Volunteers provided written informed consent before enrolment. Ethical approval for the study Clln. Drug Invest. 10 (3) 1995
174
Le ROllx rt oJ.
was obtained from the Ethics Committee of Cognacq-Jay Hospital, Paris. All volunteers were Caucasian women who had been postmenopausal for at least 3 years, with estradiol plasma levels < 30 nglL, and within IS% of their ideal body weight according the Metropolitan Insurance Company life tables. None were taking substances or had associated disorders known to affect the absorption of estradiol or the evaluation of its effects, or known to be a contraindication to transdermal estradiol replacement therapy. Study Design
The study was an open, randomised, crossover study with a washout period of 10 days between two treatment periods of 10.S days, and a final follow-up period of 1 week. During each treatment period the transdermal systems were worn for three consecutive 3.S-day periods. The transdermal systems were applied to the lower abdomen on a hairless area, the cutaneous site being changed for each new application. Procedure
Participants were treated as outpatients and came to the centre for system applications and removals and for safety evaluations. They were required to fast overnight the day before blood sampling and to avoid hot baths, strenuous exercise, caffeine, alcohol and tobacco.
Pharmacokinetic Parameters
The main pharmacokinetic parameters were calculated according to standard methods.126.271 The maximum (C max ) and minimum (C min ) plasma concentrations were measured on day 8 over the 0- to 80-hour interval during the third wear period. The areas under the plasma concentration time-curves (AUCo.8o or AUC o.!) were calculated according to the linear trapezoidal rule, t being the time of the last detectable concentration if less than 80 hours. Absolute fluctuation was calculated as C max - C min , and relative fluctuation as (C max - Cmin)1 Cav , where Cav is the average concentration, calculated by the ratio between AUCo-8o and the interval corresponding to 80 hours. Sofety Evaluation
A clinical evaluation with measurement of vital signs and a 12-lead ECG and routine laboratory tests (haematology, blood chemistry and urinalysis) were included in the screening procedure and repeated I week after the last wear period. In addition, after each system removal participants were interviewed and any adverse effect was documented on the case report form concerning severity, relationship to the study drug, date of onset and recovery, outcome and any action taken. The application site was examined after each system removal and the participants had to complete a questionnaire about the subjective symptoms experienced. Statistical Analysis
Blood Sampling
Blood samples were collected before the first and the third applications of each transdermal system, IS times at regular intervals during the third application and 1, 12, 16 and 22 hours after removal. Blood samples were centrifuged and immediately frozen at -20°e. Estradiol and estrone were assayed by capillary gas chromatography mass spectrometry with negative ionisation mode (GC-MS). Assays and statistical analyses were performed at the Centre d'Etudes et de Recherche en Pharmacie Clinique (CEPHAC), St Benoit, France. © Adis International Limited. All rights reserved.
Comparisons between the 2 centres were carried out by Student's t-test on the demographic data and baseline estradiol levels to evaluate the population homogeneity, and on the pharmacokinetic parameters to detect any centre effect. The pharmacokinetic data (Cmin, C max , AUC O-RO , Cav and relative fluctuation) of the two estrogen formulations were compared firstly by analysis of variance (3-way ANOVA: treatment, subject and period) and then by calculation of the 9S% symmetrical confidence interval limits according to Westlake and by the two I-sided t-test procedure according to Schuirmann.[28] Clin. Drug Invest. 10 (3) 1995
Bioavailability of Menorest®
175
Table I. Pharmacokinetic parameters (mean ± SO) of plasma estradiol after the third application of a 50 glday matrix transdermal system (Menorest®) or a 50 g/day reservoir transdermal system (Estraderm® TIS) in 30 postmenopausal women Reservoir system
Matrix system
Parameter
82 .73 ± 40.92
Cmax (ng/L)
p < O.OOla
29.46 ± 10.55
14.32±10.19
4572.29 ± 1817.64
4777.37 ± 1270.58
57.15 ± 22.72
60.39 ± 15.56
Cmin (ng/L) AUCO.80 (ng/Loh)
Statistical comparisons p < O.OOl a
109.62 ± 34.07
Cav (nglL)
NSa ~ = ± 13.63%b Equivalencec NSa ~ =± 13.96%b Equivalencec
[Cmax - Cminl/Cav 3-Way analysis of variance.
b
Westlake symmetrical confidence interval
c
Schuirmann two l-sided test.
p < O.OOl a
1.56 ± 0.33
0.88 ± 0.25
a
~.
Abbreviations: AUCO·80 = area under the concentration-time curve from time 0 to 80 hours; Cav = average plasma concentration ; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration ; NS = not significant at 0.05 significance level.
the pharmacokinetic results of the two centres were pooled for analysis. Based on the comparison of the AVC and Cay values for estradiol (E2) during the third wear period, i.e. at steady-state, the two formulations were equivalent in terms of total extent of availability (table I). Nevertheless, their plasma level profiles differed significantly in that plasma levels fluctuated more during the application of the reference form than during the application of Menorest®, as evidenced by the smaller mean [C max - Cminl value of Menorest® (53 .27 ± 33.74 ng/L) compared with the reference formulation (95.30 ± 33.55 nglL) and by
Time to reach C max (t max ) was compared by nonparametric analysis (Wilcoxon test). An a level of 0.05 was used for the level of statistical significance.
Results Pharmacokinetics Thirty women from two centres completed the study and I dropped out because of intercurrent influenza during the second wear period with Menorest®. After the population homogeneity had been confirmed and no centre effects had been detected,
150
•
~
en .s c 0
~ C
Q)
u
D.
120
Estraderm®: mean + so Menorest®: mean - so
90 60
c 0
u ctI
E If) ctI
a::
30 0 - 30 0
10
20
30
40
50
60
70
80
90
100
110
Time (h) Fig. 1. Plasma estradiol concentrations measured on day 8 just before and during the third application of Menorest® 50 and Estraderm® 50.
© Adis International limited. All rights reserved.
Clin. Drug Invest. 10 (3) 1995
176
Le ROllx ct nl.
Table II. Pharmacokinetic parameters (mean ± SO) of plasma estrone after the third application of a 50 glday matrix transdermal system (Menorest®) or a 50 g/day reservoir transdermal system (Estraderm® TIS) in 30 postmenopausal women Parameter
Reservoir system
Matrix system
Cmax (nglL)
56.92 ± 15.62
68.55 ± 18.90
Cmin (nglL)
32.94 ±8.71
29.99 ± 9.54
Statistical comparisons p < 0.001 a
NS a L\ ~ ± 21 .10%b
AUCO.80 (ng/L·h)
NSa
3929.88 ± 1042.69
3679.34 ± 881.61
L\ ~ ± 12.19%b
Equivalencec
Cay (nglL)
NS a
49.12±13.03
45.99 ± 11.02
L\ ~ ± 12.19%b
Equivalencec
[Cmax - CminVCav a 3-Way analysis of variance. b
Westlake symmetrical confidence interval L\.
c
Schuirmann two 1-sided test.
p < 0.001 a
0.79 ± 0.17
0.51 ± 0.22
Abbreviations: See table I.
the narrow range of mean estradiol plasma concentrations (40.03 to 72.09 ng/L) noted during the whole wear period of Menorest® compared with the 2.6-fold wider range observed after the reference formulation (18.03 to 102.28 ng/L). During the first hours of the wear period, the extent of E2 absorbed from the reservoir system exceeded that of Menorest®, resulting in a higher maximal point of the mean plasma level curve at the 37th hour, whereas the E2 plasma levels decreased more rapidly with the reservoir system down to a lower level at the 72nd hour (fig. l). 12 hours after removal of the system, the mean plasma E2 level was below 10 ng/L for both formulations.
In the estrone (E1) pharmacokinetics (table II), the two formulations were equivalent in terms of total extent of availability, but presented different plasma level profiles because of a significantly higher C max after the reservoir system; the Cmin was not significantly different with the 2 formulations. Consequently, the fluctuations in estrone plasma levels observed during Menorest® wearing were smaller than with the reservoir system (fig. 2), although the difference was less pronounced than with estradiol. The mean estradiol to estrone Cay ratios calculated for the two systems were comparable.
90
•
::::;-
Estraderm®: mean + so
b. Menorest®: mean - so
0, 75
.s c: 0
~
60
C 45 OJ u
c: 0
u III
30
E Vl
III
c::
15 0 0
10
20
30
40
50
60
70
80
90
100
110
Time (h) Fig. 2. Plasma estrone concentrations measured on day 8 just before and during the third application of Menorest® 50 and Estraderm® 50.
© Adis International Limited. All rights reserved.
Clin. Drug Invest. 10 (3) 1995
Bioavailability of Menorest®
Safety
Safety was evaluated for 30 participants during Menorest® application and for 31 participants during the reservoir system application. The number of participants who reported adverse events and the total number of events were similar with both formulations. 12 of the 33 reported events were considered by the investigators to be possibly or probably related to the study medications. All adverse events were mild or moderate in intensity and all but one (headache) concerned the genital system and consisted of metrorrhagia (3), mastodynia (5) and pelvic pain (3). No clinically relevant modification in the laboratory values was observed at the final evaluation. The percentage of participants with at least one skin reaction at the application site was higher with the reservoir system (51.6%) than with Menorest® (36.7%), principally because of a higher incidence of erythema (38 .7 vs 23.3%, respectively). Considering the total number of applications, the frequency of erythema was 18.3% with the reservoir system and 8.9% with Menorest®.
Discussion In this pharmacokinetic study, Menorest®, a new matrix-type transdermal system releasing 50f..lg of estradiol per day, was compared with a reference reservoir system during repeated applications for 10.5 days. The extent of overall absorption of estradiol and estrone (AUC o. xo and Cay) was comparable with both transdermal systems, with AUC 95% Westlake symmetrical intervals for estradiol and estrone being about 13%. The mean estradiol to estrone Cay ratios (> 1.20 in the study) are similar to and more closely resemble that of a typical menstrual cycle at the premenopausal state,1111 and confirm the fact that transdermal administration of estradiol avoids hepatic first-pass metabolism of estradiol into estrone, producing minimal induction of hepatic protein synthesis. If)
Adis International Limited. All rights reserved .
177
In contrast, oral dosage forms of estrogens require more frequent administration and higher doses to reach the expected estradiol plasma levels because of the intensity of the hepatic first-pass metabolism. This results in an estradiol to estrone ratio < I (more typical of the postmenopausal state), and in the stimulation of the hepatic synthesis of several estrogen sensitive proteins. Compared with the reservoir system, Menorest® allows a more constant absorption of estradiol over the 3.5 days of wear period resulting from a more constant release of the drug from the system. This provides plasma estradiol levels > 40 ng/L up to the 80th hour postdose, in contrast with the reservoir system, which gives wider plasma estradiol fluctuations and maintains plasma levels> 40 ng/L for only 60 hours. This observation concerning Menorest® is clinically relevant if one considers that an estradiol plasma level of 30 to 40 ng/L is the therapeutic threshold that transdermal systems should achieve in order to mimic the physiological concentrations observed during the early to mid-follicular premenopausal stage.!111 The stable and sustained plasma estradiol concentrations observed during all the wear periods correlate with the therapeutic efficacy of Menorest® in postmenopausal symptoms and long term estradiol deficiency. The patients enrolled in this study were aged 58.0 ± 4.1 years, and were postmenopausal for more than 3 years. Although the protocol stated estradiol plasma levels < 30 ng/L at screening, all women had actual values < 22 ng/L at screening. We interpret the observed metrorrhagia as Menorest® providing effective plateau concentrations of estradiol, in a similar range to that observed in premenopausal women during the early to midfollicular stage. Finally, during short term treatment the overall safety was similar for both transdermal systems, but cutaneous reactions at the site of application were more frequent with the reservoir patch (erythema being 2-fold more frequent). Clin. Drug Invest 10 (3) 1995
178
Lc ROLix ct al.
Acknowledgements Rh6ne-Poulenc Rorer provided the financial funding.
References I. Anderson F. Kinetics and pharmacology of estrogens in pre- and postmenopausal women.lntJ Ferti!1993; 38 Suppl. I: 55-64 2. Judd HL. Transdermal estradiol. A potentially improved method of hormone replacement. J Reprod Med 1994; 39 (5): 343-52 3. Lievertz RW. Pharmacology and pharmacokinetics of estrogens. Am J Obstet Gynecol 1987; 156 (5): 1289-93 4. Ettinger B, Genant HK, Cann CEo Long-term estrogen replacement therapy prevents bone loss and fractures. Ann Intern Med 1985; 102 (3): 319-24 5. Field CS, Ory SJ, Wahner HW, et al. Preventive effects of transdermal 17~-estradiol on osteoporotic changes after surgical menopause: a two-year placebo-controlled trial. Am J Obstet Gynecol 1993; 168 (I): 114-21 6. Kiel DP, Felson DT, Anderson JJ, et al. Hip fracture and the use of estrogens in postmenopausal women . The Framingham study. N Engl J Med 1987; 317 (19): 1169-74 7. Bush TL, Cowan LD, Barrett-Connor E, et al. Estrogen use and all-cause mortality. Preliminary results from the lipid research clinics program follow-up study. JAMA 1983; 249 (7): 903-6 8. Gruchow HW, Anderson AJ, Barboriak JJ, et al. Postmenopausal use of estrogen and occlusion of coronary arteries. Am Heart J 1988; 115 (5): 954-63 9. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal estrogen therapy and cardiovascular disease. Ten-year followup from nurses' health study. N Engl J Med 1991; 325 (II): 756-62 10. Sullivan JM, Zwaag RV, Lemp GF, et al. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med 1988; 108 (3): 358-63 II . Balfour JA, Heel RC. Transdermal estradiol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of menopausal complaints. Drugs 1990; 40: 561-82 12. Miller-Bass K, Adashi EY. Current status and future prospects of transdermal estrogen replacement therapy. Fertil Steri! 1990; 53 (6): 961-74 13. Cheang A, Sitruk-Ware R, Utian WHo A risk-benefit appraisal oftransderrnal estradiol therapy. Drug Saf 1993; 9 (5): 365-79 14. Geola FL, Frumar AM, Tartaryn IV, et al. Biological effects of various doses of conjugated equine estrogens in postmenopausal women. J Clin Endocrinol Metab 1980; 51 (3): 620-5
© Adis International Limited. All rights reserved.
15. Cortellaro M, Nencioni T, Boschetli C, et al. Cyclic hormonal replacement therapy after the menopause: transdermal \ersus oral treatment. Eur J Clin Pharmacol 1991; 41: 555-
Clin. Drug Jrwest, 10(3): 172-178. 1995
1173-2563/95/0009-0172 / S0350/0
© Adis Internationa l limit ed . All rights reserved
Bioavailability Study of Menorest®, a New Estrogen Transdermal Delivery System, Compared with a Transdermal Reservoir System Y. Le ROUX,l M.L. Borg,l M. Sibille,2 J. Thebault,3 A. Renoux,3 M.J. Douin,3 F Djebbarl and M.P Dain 1 1 Rhone-Poulenc Rorer, Antony, France 2 Association de Recherche TMrapeutique, Lyon, France 3 Institut Aster, Paris, France
Summary
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 membranelreservoir system (Estraderm®) and to evaluate their short term safety. This was an open, randomi sed, crossover study, with 2 treatment periods of 10.5 days separated by a IO-day washout period and with a I-week follow-up . Participants were studied at Institut Aster, Paris, and Association de Recherche Therapeutique (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 (AVC) 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 Cay 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.
Bioavailability of Menorest®
Estrogen replacement therapy (ERT) is widely recognised as being effective in relieving postmenopausal vasomotor symptoms such as hot flushes and night sweats, minimising atrophic vaginal changes,[1-3] preventing osteoporosis[4-6] and reducing the risk of cardiovascular diseases[7-1O] that occur after the exhaustion of ovarian estrogen secretion at menopause. The optimal form of ERT would have to increase 17~-estradiol (E2) plasma levels into the range observed in premenopausal women at the early or mid-follicular stage,[II] with a physiological plasma ratio of estradiol (E2) to estrone (El) of approximately 1: 1 (estradiol being the predominant estrogen produced by the ovaries). Estradiol should be delivered in a sustained manner and the amount provided should be sufficient to alleviate vasomotor symptoms, reverse atrophic vaginal changes, prevent osteoporosis, and provide cardioprotection,[12] with minimal adverse effects. Various forms of ERT are currently available: oral, topical cream or gel, suppositories, implants and transdermal delivery systems. The oral route was the first and, to date, the most widely used form,[13] while transdermal forms have been more recently developed. Oral administration of estrogens can give rise to two types of problems. The oral route requires relatively high dosages of estrogens to compensate for the extensive hepatic first-pass effect. About 60 to 90% of orally administered estrogens are converted into estrone (E I) and inactive metabolites,[3,11,14] and estrone levels are much higher than those found in premenopausal women, resulting in a decreased ratio of estradiol to estrone. High concentrations of estrogens in the portal circulation enhance the hepatic synthesis of estrogensensitive proteins with increased plasma levels of renin substrate and several hormone-binding globulins, leading to undesirable consequences such as hypertriglyceridaernia[15-17] and gallbladder diseases.l 18-20] High doses of oral estrogens decrease the plasma concentration of the main coagulation inhibitor (antithrombin III) and increase plasma levels of several coagulation factors.l 21 -24] In addi© Adis International Lim~ed . All rights reserved.
173
tion, oral ERT results in marked fluctuations above and below the desired mean serum concentrations of estradiol. [3,25] Transdermal administration of estradiol (gel and transdermal systems), which avoids first-pass hepatic metabolism, prevents some of the unwanted effects of the oral route and reduces the dose of estrogen required to achieve the expected plasma levels. However, the first reservoir/membrane system required the addition of ethanol[ll] to increase the transdermal flow of estradiol levels, with an increased risk of cutaneous reactions. Estradiol gel needs frequent administration (once daily) and it is difficult to control the area of application of the active ingredient, resulting in variability of administered doses. Menorest® (Rhone-Poulenc Rorer, Antony, France, and Collegeville, Pennsylvania, USA) is a new trans dermal system in which estradiol is uniformly dispersed in a thin (0.33mm) and transparent adhesive matrix, without alcoholic solvent. The released daily dose is proportional to the surface area: Menorest® 50 is designed to deliver 50llg! 24h of estradiol from a surface of 14.5cm2 at a constant rate over the 3 to 4 days of suggested use. The current study was carried out to compare the bioavailability and pharmacokinetic profile of Menorest® and of the reservoir/membrane transdermal system (Estraderm® TTS) using the same nominal daily delivery (50 llg/day), and to evaluate the short term safety and skin tolerability of the two products. PartiCipants and Methods Participants
Thirty-one healthy postmenopausal women, all volunteers aged between 49 and 67 years (mean age ± SO: 58.0 ± 4.1 years), participated in the study and were treated in two clinical units: Institut Aster, Cognacq-Jay Hospital, Paris, and Association de Recherche Therapeutique (ART), Lyon, France. Volunteers provided written informed consent before enrolment. Ethical approval for the study Clln. Drug Invest. 10 (3) 1995
174
Le ROllx rt oJ.
was obtained from the Ethics Committee of Cognacq-Jay Hospital, Paris. All volunteers were Caucasian women who had been postmenopausal for at least 3 years, with estradiol plasma levels < 30 nglL, and within IS% of their ideal body weight according the Metropolitan Insurance Company life tables. None were taking substances or had associated disorders known to affect the absorption of estradiol or the evaluation of its effects, or known to be a contraindication to transdermal estradiol replacement therapy. Study Design
The study was an open, randomised, crossover study with a washout period of 10 days between two treatment periods of 10.S days, and a final follow-up period of 1 week. During each treatment period the transdermal systems were worn for three consecutive 3.S-day periods. The transdermal systems were applied to the lower abdomen on a hairless area, the cutaneous site being changed for each new application. Procedure
Participants were treated as outpatients and came to the centre for system applications and removals and for safety evaluations. They were required to fast overnight the day before blood sampling and to avoid hot baths, strenuous exercise, caffeine, alcohol and tobacco.
Pharmacokinetic Parameters
The main pharmacokinetic parameters were calculated according to standard methods.126.271 The maximum (C max ) and minimum (C min ) plasma concentrations were measured on day 8 over the 0- to 80-hour interval during the third wear period. The areas under the plasma concentration time-curves (AUCo.8o or AUC o.!) were calculated according to the linear trapezoidal rule, t being the time of the last detectable concentration if less than 80 hours. Absolute fluctuation was calculated as C max - C min , and relative fluctuation as (C max - Cmin)1 Cav , where Cav is the average concentration, calculated by the ratio between AUCo-8o and the interval corresponding to 80 hours. Sofety Evaluation
A clinical evaluation with measurement of vital signs and a 12-lead ECG and routine laboratory tests (haematology, blood chemistry and urinalysis) were included in the screening procedure and repeated I week after the last wear period. In addition, after each system removal participants were interviewed and any adverse effect was documented on the case report form concerning severity, relationship to the study drug, date of onset and recovery, outcome and any action taken. The application site was examined after each system removal and the participants had to complete a questionnaire about the subjective symptoms experienced. Statistical Analysis
Blood Sampling
Blood samples were collected before the first and the third applications of each transdermal system, IS times at regular intervals during the third application and 1, 12, 16 and 22 hours after removal. Blood samples were centrifuged and immediately frozen at -20°e. Estradiol and estrone were assayed by capillary gas chromatography mass spectrometry with negative ionisation mode (GC-MS). Assays and statistical analyses were performed at the Centre d'Etudes et de Recherche en Pharmacie Clinique (CEPHAC), St Benoit, France. © Adis International Limited. All rights reserved.
Comparisons between the 2 centres were carried out by Student's t-test on the demographic data and baseline estradiol levels to evaluate the population homogeneity, and on the pharmacokinetic parameters to detect any centre effect. The pharmacokinetic data (Cmin, C max , AUC O-RO , Cav and relative fluctuation) of the two estrogen formulations were compared firstly by analysis of variance (3-way ANOVA: treatment, subject and period) and then by calculation of the 9S% symmetrical confidence interval limits according to Westlake and by the two I-sided t-test procedure according to Schuirmann.[28] Clin. Drug Invest. 10 (3) 1995
Bioavailability of Menorest®
175
Table I. Pharmacokinetic parameters (mean ± SO) of plasma estradiol after the third application of a 50 glday matrix transdermal system (Menorest®) or a 50 g/day reservoir transdermal system (Estraderm® TIS) in 30 postmenopausal women Reservoir system
Matrix system
Parameter
82 .73 ± 40.92
Cmax (ng/L)
p < O.OOla
29.46 ± 10.55
14.32±10.19
4572.29 ± 1817.64
4777.37 ± 1270.58
57.15 ± 22.72
60.39 ± 15.56
Cmin (ng/L) AUCO.80 (ng/Loh)
Statistical comparisons p < O.OOl a
109.62 ± 34.07
Cav (nglL)
NSa ~ = ± 13.63%b Equivalencec NSa ~ =± 13.96%b Equivalencec
[Cmax - Cminl/Cav 3-Way analysis of variance.
b
Westlake symmetrical confidence interval
c
Schuirmann two l-sided test.
p < O.OOl a
1.56 ± 0.33
0.88 ± 0.25
a
~.
Abbreviations: AUCO·80 = area under the concentration-time curve from time 0 to 80 hours; Cav = average plasma concentration ; Cmax = maximum plasma concentration; Cmin = minimum plasma concentration ; NS = not significant at 0.05 significance level.
the pharmacokinetic results of the two centres were pooled for analysis. Based on the comparison of the AVC and Cay values for estradiol (E2) during the third wear period, i.e. at steady-state, the two formulations were equivalent in terms of total extent of availability (table I). Nevertheless, their plasma level profiles differed significantly in that plasma levels fluctuated more during the application of the reference form than during the application of Menorest®, as evidenced by the smaller mean [C max - Cminl value of Menorest® (53 .27 ± 33.74 ng/L) compared with the reference formulation (95.30 ± 33.55 nglL) and by
Time to reach C max (t max ) was compared by nonparametric analysis (Wilcoxon test). An a level of 0.05 was used for the level of statistical significance.
Results Pharmacokinetics Thirty women from two centres completed the study and I dropped out because of intercurrent influenza during the second wear period with Menorest®. After the population homogeneity had been confirmed and no centre effects had been detected,
150
•
~
en .s c 0
~ C
Q)
u
D.
120
Estraderm®: mean + so Menorest®: mean - so
90 60
c 0
u ctI
E If) ctI
a::
30 0 - 30 0
10
20
30
40
50
60
70
80
90
100
110
Time (h) Fig. 1. Plasma estradiol concentrations measured on day 8 just before and during the third application of Menorest® 50 and Estraderm® 50.
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Clin. Drug Invest. 10 (3) 1995
176
Le ROllx ct nl.
Table II. Pharmacokinetic parameters (mean ± SO) of plasma estrone after the third application of a 50 glday matrix transdermal system (Menorest®) or a 50 g/day reservoir transdermal system (Estraderm® TIS) in 30 postmenopausal women Parameter
Reservoir system
Matrix system
Cmax (nglL)
56.92 ± 15.62
68.55 ± 18.90
Cmin (nglL)
32.94 ±8.71
29.99 ± 9.54
Statistical comparisons p < 0.001 a
NS a L\ ~ ± 21 .10%b
AUCO.80 (ng/L·h)
NSa
3929.88 ± 1042.69
3679.34 ± 881.61
L\ ~ ± 12.19%b
Equivalencec
Cay (nglL)
NS a
49.12±13.03
45.99 ± 11.02
L\ ~ ± 12.19%b
Equivalencec
[Cmax - CminVCav a 3-Way analysis of variance. b
Westlake symmetrical confidence interval L\.
c
Schuirmann two 1-sided test.
p < 0.001 a
0.79 ± 0.17
0.51 ± 0.22
Abbreviations: See table I.
the narrow range of mean estradiol plasma concentrations (40.03 to 72.09 ng/L) noted during the whole wear period of Menorest® compared with the 2.6-fold wider range observed after the reference formulation (18.03 to 102.28 ng/L). During the first hours of the wear period, the extent of E2 absorbed from the reservoir system exceeded that of Menorest®, resulting in a higher maximal point of the mean plasma level curve at the 37th hour, whereas the E2 plasma levels decreased more rapidly with the reservoir system down to a lower level at the 72nd hour (fig. l). 12 hours after removal of the system, the mean plasma E2 level was below 10 ng/L for both formulations.
In the estrone (E1) pharmacokinetics (table II), the two formulations were equivalent in terms of total extent of availability, but presented different plasma level profiles because of a significantly higher C max after the reservoir system; the Cmin was not significantly different with the 2 formulations. Consequently, the fluctuations in estrone plasma levels observed during Menorest® wearing were smaller than with the reservoir system (fig. 2), although the difference was less pronounced than with estradiol. The mean estradiol to estrone Cay ratios calculated for the two systems were comparable.
90
•
::::;-
Estraderm®: mean + so
b. Menorest®: mean - so
0, 75
.s c: 0
~
60
C 45 OJ u
c: 0
u III
30
E Vl
III
c::
15 0 0
10
20
30
40
50
60
70
80
90
100
110
Time (h) Fig. 2. Plasma estrone concentrations measured on day 8 just before and during the third application of Menorest® 50 and Estraderm® 50.
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Clin. Drug Invest. 10 (3) 1995
Bioavailability of Menorest®
Safety
Safety was evaluated for 30 participants during Menorest® application and for 31 participants during the reservoir system application. The number of participants who reported adverse events and the total number of events were similar with both formulations. 12 of the 33 reported events were considered by the investigators to be possibly or probably related to the study medications. All adverse events were mild or moderate in intensity and all but one (headache) concerned the genital system and consisted of metrorrhagia (3), mastodynia (5) and pelvic pain (3). No clinically relevant modification in the laboratory values was observed at the final evaluation. The percentage of participants with at least one skin reaction at the application site was higher with the reservoir system (51.6%) than with Menorest® (36.7%), principally because of a higher incidence of erythema (38 .7 vs 23.3%, respectively). Considering the total number of applications, the frequency of erythema was 18.3% with the reservoir system and 8.9% with Menorest®.
Discussion In this pharmacokinetic study, Menorest®, a new matrix-type transdermal system releasing 50f..lg of estradiol per day, was compared with a reference reservoir system during repeated applications for 10.5 days. The extent of overall absorption of estradiol and estrone (AUC o. xo and Cay) was comparable with both transdermal systems, with AUC 95% Westlake symmetrical intervals for estradiol and estrone being about 13%. The mean estradiol to estrone Cay ratios (> 1.20 in the study) are similar to and more closely resemble that of a typical menstrual cycle at the premenopausal state,1111 and confirm the fact that transdermal administration of estradiol avoids hepatic first-pass metabolism of estradiol into estrone, producing minimal induction of hepatic protein synthesis. If)
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177
In contrast, oral dosage forms of estrogens require more frequent administration and higher doses to reach the expected estradiol plasma levels because of the intensity of the hepatic first-pass metabolism. This results in an estradiol to estrone ratio < I (more typical of the postmenopausal state), and in the stimulation of the hepatic synthesis of several estrogen sensitive proteins. Compared with the reservoir system, Menorest® allows a more constant absorption of estradiol over the 3.5 days of wear period resulting from a more constant release of the drug from the system. This provides plasma estradiol levels > 40 ng/L up to the 80th hour postdose, in contrast with the reservoir system, which gives wider plasma estradiol fluctuations and maintains plasma levels> 40 ng/L for only 60 hours. This observation concerning Menorest® is clinically relevant if one considers that an estradiol plasma level of 30 to 40 ng/L is the therapeutic threshold that transdermal systems should achieve in order to mimic the physiological concentrations observed during the early to mid-follicular premenopausal stage.!111 The stable and sustained plasma estradiol concentrations observed during all the wear periods correlate with the therapeutic efficacy of Menorest® in postmenopausal symptoms and long term estradiol deficiency. The patients enrolled in this study were aged 58.0 ± 4.1 years, and were postmenopausal for more than 3 years. Although the protocol stated estradiol plasma levels < 30 ng/L at screening, all women had actual values < 22 ng/L at screening. We interpret the observed metrorrhagia as Menorest® providing effective plateau concentrations of estradiol, in a similar range to that observed in premenopausal women during the early to midfollicular stage. Finally, during short term treatment the overall safety was similar for both transdermal systems, but cutaneous reactions at the site of application were more frequent with the reservoir patch (erythema being 2-fold more frequent). Clin. Drug Invest 10 (3) 1995
178
Lc ROLix ct al.
Acknowledgements Rh6ne-Poulenc Rorer provided the financial funding.
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15. Cortellaro M, Nencioni T, Boschetli C, et al. Cyclic hormonal replacement therapy after the menopause: transdermal \ersus oral treatment. Eur J Clin Pharmacol 1991; 41: 555-
