Pharmacokinetics of oestriol cream using quantitative liquid chromatography tandem mass spectrometry

te West N1, Allen W1, Day R2, Graham G2, Parkin K1, White C3, Moore K1

Research Type

Clinical

Abstract Category

Pharmacology

Abstract 392
E-Poster 2
Scientific Open Discussion ePoster Session 18
Thursday 5th September 2019
13:45 - 13:50 (ePoster Station 10)
Exhibition Hall
Hormone Therapy Pelvic Floor Pharmacology
1.Department of Urogynaecology, St George Hospital, School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia, 2.Department of Clinical Pharmacology and Toxicology, University of New South Wales, St. Vincent’s Hospital, Sydney, Australia, 3.SEALS Clinical Chemistry and Endocrinology, Prince of Wales Hospital, Sydney, Australia
Presenter
N

Nevine te West

Links

Poster

Abstract

Hypothesis / aims of study
Vaginal oestriol (E3) cream is often prescribed by Urologists and Urogynaecologists to treat women with urinary incontinence, prolapse, and/ or recurrent cystitis, with proven benefit. However, after the publication of the association between oral oestrogen and breast cancer (1), patients often enquire about safety, and primary caregivers are reluctant to prescribe it despite the known benefit. Previous studies demonstrating that E3 cream is safe, relied on demonstrating serum E3 levels below the traditional postmenopausal threshold of 100 pmol/L in current cream users (2). However, these measurements were performed using radioimmunoassay (RIA), which was originally used for infertility investigations in women with much higher levels of oestrogens compared to post-menopausal patients. Specificity and sensitivity of RIA are low, particularly post-menopause when the concentration of circulating oestrogens is reduced and the “upper limit” (100 pmol/L) may have simply reflected the lower limit of quantitation (LLOQ) of these earlier assays. With the modern development of quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) assays, changes in serum E3 levels in vaginal E3 cream users can be measured much more accurately than with the previously used RIA. 

The aim of this exploratory study was to measure the pharmacokinetic (PK) profile of E3 cream by assessing the interindividual and intraindividual differences before, and for a 24-hour period after, E3 cream application. We hypothesised that serum levels could transiently increase to >100pmol/L, but should not remain elevated for more than 8 hours and return to pre-E3 cream levels within 24 hours.
Study design, materials and methods
The study consisted of 10 post-menopausal women who had been applying oestriol cream 2-3 times a week for at least 12 weeks for urogynaecological complaints. We requested they omit the cream for at least 36 hours prior to the study. These women attended our unit at 8am. A cannula was sited and a first sample of serum taken at baseline for E3 measurement (0 hours). They were then asked to measure E3 cream with the applicator to achieve a dose of 0.5mg and apply this to the lower 1/3 of vagina digitally, rather than inserting the cream high in the vagina, which has been shown to increase systemic absorption (first pass uterine effect (3)). Subsequently, serum was taken at 1, 2, 3, 5, 8, 10 and 12 hours post cream application, the patients went home for the night, returned to the unit at 8am when the last serum sample taken for E3 levels (24 hours). Samples were stored in duplicate at -80°C until transported to the laboratory. The LLOQ of the LC-MS/MS assay is 5 pmol/L (CV 5%). In order to evaluate intraindividual differences in E3, 5 of the 10 women, had the same procedure repeated within a median of 9 months (IQR 2-13).
Results
Of the 10 recruits, 3 patients yielded an incomplete PK series: 1 could not return at 24 hours and 2 other women’s cannulas failed and despite multiple attempts we could not obtain an adequate sample by venepuncture. The women had been using E3 cream for a median of 26 months (IQR 12-46). Median vaginal pH levels measured 4.7 (IQR4.4-5.0). Oestriol levels fell to <100pmol/L in the majority of women (6/10) within 8 hours with the available samples. At 24 hours all women demonstrated oestriol levels less than 10pmol/L. The area under the curve was also calculated: median 2175 (IQR 1181-3607).
Interindividual variability for peak levels was high: range 245.1-1066.4 pmol/L (Table 1 and Fig 1). Intraindividual variations were less marked in 5 women that repeated the PK study, with similar peaks during the two 24-hour periods. Most of the peaks in serum E3 levels occurred 2 hours post application but could range from 1-5 hours. Liver and kidney function were normal in all patients but one. No association was found between levels of E3 and BMI.
Interpretation of results
To our knowledge a study using this precise analytical technology to assess E3 serum PK levels has not previously been performed to explore peak E3 levels in postmenopausal women. The majority (6/10) had E3 serum levels <100pmol/L 8 hours after application, however there was great variation between patients but less intraindividual variation. This suggests that patients proven to have peaks within a nominal therapeutic range may be expected to have reproducible PK profile, but that dose and response to therapy may need to be individualised. Theoretically, chronic users were thought to have less E3 absorption following adaptation/ cornification of the epithelium from E3 exposure. However, 4 patients demonstrated pronounced differences in absorption profiles with peak levels confirming wide interindividual variations in E3 Pharmacokinetics in postmenopausal women.
Concluding message
In this novel study we found serum E3 levels of women using E3 cream as a chronic treatment to vary greatly between users, but less so within single users who were measured twice. The majority of women had E3 levels below 100 pmol/L after 8 hours.
Figure 1 Table 1: E3 levels in pmol/L. NS= no sample. a and b represent the test-retest samples of same patient
Figure 2 Fig 1: E3 levels plotted in pmol/L against hours. Same colour for test-retest levels.
References
  1. Chlebowski, R.T., et al., Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. Jama, 2003. 289(24): p. 3243-53.
  2. Mattsson, L.A. and G. Cullberg, Vaginal absorption of two estriol preparations. A comparative study in postmenopausal women. Acta Obstet Gynecol Scand, 1983. 62(5): p. 393-6.
  3. Cicinelli, E., et al., Placement of the vaginal 17beta-estradiol tablets in the inner or outer one third of the vagina affects the preferential delivery of 17beta-estradiol toward the uterus or periurethral areas, thereby modifying efficacy and endometrial safety. Am J Obstet Gynecol, 2003. 189(1): p. 55-8.
Disclosures
Funding A grant received from the Australian Bladder Foundation was used for covering patients' parking costs and meals and refreshments during the time spent at the clinical unit during the study Clinical Trial No Subjects Human Ethics Committee South East Area Sydney and Illawarra Human Research Ethics Committee, Southern Section Helsinki Yes Informed Consent Yes