Pharmacokinetics
Conditions
Keywords
contraceptive ring, obesity, pharmacokinetics, pharmacodynamics, Pharmacokinetics of the contraceptive ring in obese women.
Brief summary
There are over 60 million women of reproductive age in the U.S. and a majority of these women qualify as overweight or obese. Evidence suggests that there is an association between increased body weight and decreased contraceptive efficacy. Studies with the combined hormonal contraceptive patch (Evra®) and the subdermal contraceptive implant (Norplant®) demonstrate higher failure rates in heavier versus lighter women. Weight related differences in the effectiveness of NuvaRing® need further study. A single secondary analysis of pooled data from Phase III clinical trials of NuvaRing® noted no difference in pregnancy rates among women in the highest weight decile (\>166#) versus the rest of the study population using the ring. (Westhoff, 2005) The finding of no difference, however, was influenced by too few obese subjects in the analysis which contributed to wide confidence limits. Additional studies are needed to explore how well the contraceptive ring functions to maintain effective serum steroid concentrations to suppress ovarian activity in obese women. This investigation focused on evaluating mean serum concentrations of hormones released in obese and normal weight women using the NuvaRing® . This study was a prospective clinical trial. Normal weight women are defined as women with a BMI 19-24.9 and obese women are those with a BMI 30-39.9. We recruited forty adult women interested in initiating the combined hormonal contraceptive ring to two months of use to complete analysis of at least 34 subjects (17 normal weight, 17 obese). We compared mean serum concentrations of ethinyl estradiol (E2) and etonogestrel (ENG) along with additional markers for ovarian suppression. These markers included sonographic evidence of follicular development and ovulation as well as circulating E2 levels which strongly correlate with follicular development and endometrial proliferation during the second month of NuvaRing® use. Assessment of these parameters will translated to understanding contraceptive-mediated suppression of ovarian function in these two groups. Subjects also logged patterns of ring use and bleeding patterns during the study period.
Interventions
DRUGNuvaRing
Obese subjects (BMI 30-39.9) will receive two contraceptive hormonal rings. During the second cycle of ring use, subjects will return to the study site for serial serum hormone measurements and transvaginal ultrasound twice weekly during four weeks of continuous use.
Sponsors
Organon
Columbia University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
Yes
Inclusion criteria
* 18-35 yo * Meet BMI requirements * Weight stable * English speaking * Desire contraception * History of regular menses with normal uterus and ovaries * Medically eligible for combined hormonal contraception * Tolerates phlebotomy/TVS
Exclusion criteria
* Exclusion: * Heavy smokers * Users of medications that alter hormone levels
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Measurements at Week 3 and Week 6 continuous ring use | Serum concentrations were obtained from thirty-seven women completed follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving a Maximum Follicle Diameter > 13mm During the 3 Weeks of Follow-up | continuous ring use, an average of 3 weeks | Follicular development was minimal in both groups, with only five women achieving a maximum follicle diameter \> 13mm at any time during the 3 weeks of follow-up (3 normal weight and 2 obese women). |
| Mean Endometrial Proliferation | Transvaginal ultrasound measurements of endometrial proliferation will be completed over continuous ring use, an average of 3 weeks | The mean endometrial proliferation from week 1, week 2 and week3 |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled during the months of June-September 2008.
Participants by arm
| Arm | Count |
|---|---|
| Obese Subjects Obese subjects (BMI 30-39.9) | 20 |
| Normal Weight Subjects Normal weight subjects (BMI 19-24.9) | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
Baseline characteristics
| Characteristic | Total | Obese Subjects | Normal Weight Subjects |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 40 Participants | 20 Participants | 20 Participants |
| Age, Continuous | 25.8 years STANDARD_DEVIATION 3.7 | 24.5 years STANDARD_DEVIATION 3.2 | 26.0 years STANDARD_DEVIATION 3.6 |
| Region of Enrollment United States | 40 participants | 20 participants | 20 participants |
| Sex: Female, Male Female | 40 Participants | 20 Participants | 20 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 2 / 20 |
Outcome results
Primary
Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol
Serum concentrations were obtained from thirty-seven women completed follow-up.
Time frame: Measurements at Week 3 and Week 6 continuous ring use
Population: 17 participants in each group was planned a priori to have 80% power to identify a one standard deviation difference in the mean serum levels of the contraceptive hormones. We enrolled 40 women, 2 withdrew prior to the study cycle. We excluded one woman due to removal of the CVR during the study cycle leaving 18 normal weight and 19 obese women.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Normal Weight | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Etonogesterel (ENG) Week 3 | 1275 ng/L |
| Normal Weight | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Ethinyl Estradiol (EE) Week 3 | 21.9 ng/L |
| Normal Weight | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Etonogesterel (ENG) Week 6 | 1063 ng/L |
| Normal Weight | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Ethinyl Estradiol (EE) Week 6 | 16.2 ng/L |
| Obese | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Ethinyl Estradiol (EE) Week 6 | 12.5 ng/L |
| Obese | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Etonogesterel (ENG) Week 3 | 1240 ng/L |
| Obese | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Etonogesterel (ENG) Week 6 | 1096 ng/L |
| Obese | Mean Serum Concentrations of Etonogestrel and Ethinyl Estradiol | Ethinyl Estradiol (EE) Week 3 | 14.8 ng/L |
Secondary
Mean Endometrial Proliferation
The mean endometrial proliferation from week 1, week 2 and week3
Time frame: Transvaginal ultrasound measurements of endometrial proliferation will be completed over continuous ring use, an average of 3 weeks
Population: 17 participants in each group was planned a priori to have 80% power to identify a one standard deviation difference in the mean serum levels of the contraceptive hormones. We enrolled 40 women, 2 withdrew prior to the study cycle. We excluded one woman due to removal of the CVR during the study cycle leaving 18 normal weight and 19 obese women.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Weight | Mean Endometrial Proliferation | 4.7 millimeters | Standard Deviation 1.8 |
| Obese | Mean Endometrial Proliferation | 3.9 millimeters | Standard Deviation 1.6 |
Secondary
Number of Participants Achieving a Maximum Follicle Diameter > 13mm During the 3 Weeks of Follow-up
Follicular development was minimal in both groups, with only five women achieving a maximum follicle diameter \> 13mm at any time during the 3 weeks of follow-up (3 normal weight and 2 obese women).
Time frame: continuous ring use, an average of 3 weeks
Population: 17 participants in each group was planned a priori to have 80% power to identify a one standard deviation difference in the mean serum levels of the contraceptive hormones. We enrolled 40 women, 2 withdrew prior to the study cycle. We excluded one woman due to removal of the CVR during the study cycle leaving 18 normal weight and 19 obese women.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Normal Weight | Number of Participants Achieving a Maximum Follicle Diameter > 13mm During the 3 Weeks of Follow-up | 2 Participant w/follicular diameter >=13mm |
| Obese | Number of Participants Achieving a Maximum Follicle Diameter > 13mm During the 3 Weeks of Follow-up | 3 Participant w/follicular diameter >=13mm |