Abstract
Objective:
To evaluate topiramate and etonogestrel pharmacokinetic interactions in contraceptive implant users.
Methods:
We conducted a prospective, non-inferiority study with healthy females using etonogestrel implants continuously for 12-36 months. We measured baseline serum etonogestrel concentrations and then began a 6-week titrated topiramate regimen to standard migraine (100 mg/day) and epilepsy (400 mg/day) dosages. We repeated serum etonogestrel concentrations at 3 weeks (100mg/day), 4 weeks (200mg/day), and 6 weeks (400mg/day) of topiramate therapy. We measured etonogestrel using a validated liquid chromatography-tandem mass-spectrometry assay and tested for non-inferiority (<30% decrease) in serum etonogestrel concentrations from baseline.
Results:
We enrolled 48 total participants; 32 completed 3-weeks, 31 completed 4-weeks, and 27 completed all follow-ups. Participants’ median age was 25.3 years (range 18.3-37.2), median BMI was 25.5kg/m2 (range 18.7-42.2), and median duration of implant use was 24 months (range 12-36). Median etonogestrel concentrations were 142pg/mL (range 76.2-771) at baseline, 126pg/mL (range 72.4-585) at three weeks, 119pg/mL (range 65.6-542) at four weeks, and 105pg/mL (46.2-859) at six weeks. The 95% confidence intervals for mean percent change in serum etonogestrel concentrations from baseline were [−37.3%, +16.9%], [−45.4%, +5.2%], and [−66.8%, +24.8%] at three weeks, four weeks, and six weeks, respectively. Excluding one participant who had a serum etonogestrel concentration <90pg/mL at baseline, 30.8% of participants (8/26, 95% CI 14.3%-51.8%) had a serum etonogestrel concentration <90pg/mL at six weeks.
Conclusions:
Though only a mild EIAED, concomitant topiramate use led to inferior serum etonogestrel concentrations among implant users, with a significant proportion reaching etonogestrel concentrations below the threshold for ovulatory suppression when taking anti-epileptic dosages of topiramate.
Precis:
Topiramate has a significant drug interaction with the etonogestrel contraceptive implant that may result in contraceptive failures at higher dosages.
Introduction
Topiramate is an anti-epileptic drug first designated as treatment for partial-onset seizures and primary generalized tonic-clonic seizures (1). Its main use currently is for migraine prevention: topiramate is considered a first-line treatment for migraine prophylaxis, along with β-blockers and valproate (2–4). The majority of patients afflicted by chronic migraines are reproductive age females who would require reliable contraception if prescribed topiramate given the potential teratogenicity of this medication (5). Topiramate use during pregnancy has been associated with increased risks of cleft lip and palate among human infants and animal studies have also found increased risks of craniofacial structural malformations and reduced fetal weights in exposed offspring (1). A complicating factor for contraceptive use in migraineurs with associated aura (complex migraine) is the contraindication to the use of estrogen-containing contraceptive methods due to the increased risk of stroke (6). Thus, highly effective progestin-only contraceptive methods, like the etonogestrel contraceptive implant, could be ideal for this specific population.
Topiramate is also a known enzyme-inducing anti-epileptic drug (EIAED) and causes induction of cytochrome P-450 (CYP) 3A enzymes in the liver. For purposes of contraceptive counseling, topiramate is included in a broad category of EIAEDs with phenytoin, barbiturates, and carbamazepine (6). Many of these EIAEDs have well documented strong CYP-3A induction properties and consistent pharmacokinetic effects of decreasing serum contraceptive hormone levels (7). Carbamazepine, for example, causes clinically significant reductions in serum etonogestrel concentrations among contraceptive implant users and has been associated with case reports of unintended pregnancy due to contraceptive implant failure (8, 9). Unlike carbamazepine, topiramate has far less pharmacokinetic data in the literature to support that its CYP induction properties have clinical implications. There are only two small, published studies that investigated topiramate’s pharmacokinetic effect on a combined oral contraceptive pill (10, 11). Both studies found decreases in serum ethinyl estradiol concentrations (mean area under the curve measurements ranging from 9% to 30% lower) with concomitant topiramate use, but no significant pharmacokinetic effect of topiramate on norethindrone concentrations (10, 11).
The limited data from these contraceptive pill studies suggest that topiramate’s drug-drug interaction differs significantly from other EIAEDs, yet current clinical resources provide identical recommendations for these medications (6). Given the potential teratogenicity of topiramate, and the limited contraceptive options available to women with complex migraine or seizure disorder, it is imperative that reproductive age females prescribed topiramate receive appropriate counseling on the contraceptive options available to them. The etonogestrel contraceptive implant (Nexplanon®, Merck & Co., Whitehouse Station NJ) is the most efficacious hormonal contraceptive method and is also an ideal contraceptive method for drug interaction studies given its steady-release pharmacokinetics and lack of compliance issues (12, 13). We evaluated the drug-drug interaction between topiramate and the etonogestrel contraceptive implant and hypothesized that topiramate would not cause a potentially clinically significant reduction in serum etonogestrel concentrations.
Methods
We conducted a prospective, non-inferiority study to evaluate the pharmacokinetic effect of topiramate on serum etonogestrel concentrations among contraceptive implant users. We recruited healthy, reproductive age (18-45 years) females using an etonogestrel implant for at least 12 months and no longer than 36 months. We selected this duration of implant use due to the pharmacokinetic burst following etonogestrel implant insertion that resolves to a relative steady-state by 12 months (12). We excluded females using medications or supplements that inhibit or induce CYP-3A4 (14) or with a body-mass index (BMI) <18.5kg/m2, due to concerns for altered drug metabolism among underweight individuals. We also excluded females with any hepatic or renal dysfunction as determined by a comprehensive metabolic panel (defined as alanine aminotransferase >52U/L, aspartate aminotransferase >39U/L, or serum creatinine >1.2mg/dL) or based on any history of hepatic or renal disease, such as hepatitis, cirrhosis, or kidney transplant. As topiramate use can cause the rare side effect of metabolic acidosis, we screened potential participants for low serum bicarbonate as part of the comprehensive metabolic panel and excluded any participants with a bicarbonate <21mmol/L (1). All participants were current etonogestrel implant users who agreed to take topiramate solely for the purposes of this study and were counseled on the risks of taking topiramate prior to initiating the study drug. The protocol was approved by the Colorado Multiple Institutional Review Board and all participants gave written informed consent before study initiation. We recruited participants through local advertising and contraceptive clinics at a large academic institution in Denver, CO.
At the time of enrollment, we measured participants’ height and weight to calculate their BMI and assessed duration of implant use based on electronic health record review or by participant report if health records were not available. We ensured current etonogestrel implant use by direct palpation of the implant and reviewed each participant’s medical history and current medications and supplements to confirm eligibility for this study. Participants could not be pregnant or planning to become pregnant during the study and we screened all participants with a urine pregnancy test at enrollment and every subsequent study visit. Participants meeting all non-laboratory inclusion and exclusions criteria then underwent a single, baseline blood draw to obtain whole blood and serum. A portion of this blood sample was sent to our academic hospital clinical laboratory for the comprehensive metabolic panel. The remaining blood collected was allowed to clot for at least 10 minutes at room temperature before undergoing centrifugation for extraction of serum. We then stored serum in aliquots at −80°F for eventual baseline (Visit 1) serum etonogestrel concentration analysis. The research team determined final study eligibility after review of the comprehensive metabolic panel based on our pre-defined laboratory exclusion criteria. Eligible participants could then receive the first course of study medication (topiramate) either by picking up the medication from our research clinic or by having the medication directly mailed to them.
Participants then began a 6-week titration schedule of oral topiramate to a max dose of 200mg twice a day by the final week (see Appendix 1, available online at http://links.lww.com/xxx, for the full titration schedule). Topiramate is typically prescribed at a total daily dose of 100mg or 200mg for treatment or prevention of migraines, which was achieved in the third and fourth week of the titration schedule, respectively (2, 4). The maximum recommended dose of topiramate for treatment of epilepsy is 400mg per day, which was achieved in the sixth and final week of the titration schedule (1). All participants returned at the end of the third week of the topiramate titration schedule for Visit 2. At Visit 2, participants underwent a repeat single-time blood draw, a portion of which was used for measurement of serum topiramate concentration at ARUP® Laboratories (Salt Lake City, Utah) as a measurement of compliance. This topiramate concentration testing was performed through routine clinical pathways of our academic hospital laboratory using a quantitative enzyme immunoassay at the referral lab. Similar to Visit 1, serum obtained from this blood draw was stored at −80°F for eventual serum etonogestrel concentration analysis. We also screened all participants for adverse events at this follow-up visit and gave participants the next course of topiramate to continue the titration schedule.
All participants then returned at the end of the fourth and sixth week of the titration schedule for Visit 3 and Visit 4, respectively. We performed repeat single-time blood draws at these visits and again measured serum topiramate concentrations for compliance. Serum was obtained for each visit and stored at −80°F for eventual serum etonogestrel concentration analysis. Participants had to present for the fourth week visit in order to obtain the final course of topiramate for the titration schedule. After Visit 4, participants underwent a seven-day withdrawal titration schedule (see Appendix 1, http://links.lww.com/xxx) due to a known association between abrupt topiramate cessation and increases in seizure episodes among patients prescribed topiramate for epilepsy. All participants were required to use a back-up non-hormonal contraceptive method or abstain from intercourse during the study and for three weeks after completing the withdrawal titration schedule.
At the conclusion of enrollment and all follow-up visits, we de-identified all stored serum samples and assigned all samples a randomly generated three letter identification code to remove any potential for bias in analysis based on samples from the same participant or based on timing of sample collection. We then shipped all stored serum samples to the Q Squared Solutions laboratory in Ithaca, New York. Serum samples underwent etonogestrel concentration analysis using a validated liquid chromatography tandem mass-spectrometry methodology (15). Samples underwent liquid-liquid extraction and were then chromatographed using reversed phase high performance liquid chromatography with detection via tandem mass spectrometry employing a turbo ion spray interface in the positive ion mode. The lower limit of quantitation was 20.0pg/mL and internal standards and quality controls were included in the analysis. We batched samples for analysis to reduce inter-assay variability and all laboratory personnel were blinded to sample relatedness and timing.
We used IBM SPSS™ version 27 statistical software for our analyses. We performed descriptive frequencies for participant characteristics, serum etonogestrel concentrations, and serum topiramate concentrations at each visit. To assess non-inferiority, we calculated percent changes in serum etonogestrel concentrations from baseline to each subsequent visit for all participants. We then calculated the mean and range percent change in serum etonogestrel concentrations among all participants with available data at each visit. As serum etonogestrel concentrations are not normally distributed, we converted this median and range data to mean and standard deviation using the method developed by Hozo et al (16). We then calculated the 95% confidence interval for the mean percent change in serum etonogestrel concentrations at each visit to determine non-inferiority. For this study, non-inferiority was defined as a change in serum etonogestrel concentrations at the maximum dose of topiramate that would not result in concentrations below the threshold for ovulatory suppression (<90pg/mL) (12). We chose a non-inferiority limit of 30% because this level of decrease from the median published levels (137-207pg/mL) would not cross this threshold (17, 18).
Given the non-normal distribution of etonogestrel concentrations, we also used the non-parametric, related-samples Friedman’s test to compare serum etonogestrel concentrations across the visits using each participant as their own control. We also performed a sub-group analysis (Friedman’s test) of only participants who reached a therapeutic topiramate concentration (≥5μg/mL) at any follow-up visit. We calculated that we would need a sample size of 27 participants for our selected non-inferiority limit of 30% with an alpha level of 0.05 and beta of 0.9 for our primary outcome of comparing baseline serum etonogestrel concentrations to etonogestrel concentrations at the end of the 6-week topiramate titration schedule (200mg twice a day dose). We used a higher beta cut-off to account for the use of a statistical sample size calculation based on a normal distribution, when serum etonogestrel concentrations has a known non-normal distribution. We planned to enroll up to 53 participants to account for a potential 49% drop-out and non-compliance rate, which accounted for an expected 30% intolerance rate for topiramate doses >200mg per day.
Role of the Funding Source
All funding sources listed had no involvement in the study design, collection, analysis, interpretation of data, writing of this report, or decision to submit this article for publication. The authors had access to relevant aggregated study data and other information (such as study protocol, analytic plan and report, validated data table, and clinical study report) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors’ personal interests, financial or non-financial, relating to this research and its publication have been disclosed.
Results
Between April 2018 and October 2020, we screened 80 potential participants for this study and enrolled 48 total participants. Figure 1 provides a flow diagram of study enrollment. We had 32 participants complete Visit 2 (100 mg/day of topiramate), 31 complete Visit 3 (200 mg/day), and 27 complete Visit 4 (400 mg/day). Table 1 provides participant demographics and characteristics for the 32 participants who completed at least one follow-up visit. Participants were relatively young (median age of 25.3 years [range 18.3-37.2]), with a median BMI of 25.5kg/m2 (range 18.7-42.2) and median duration of implant use of 24 months (range 12-36).
Figure 1:
Flow diagram for participant screening, enrollment, and follow-up.
Table 1:
Demographics and characteristics of participants using etonogestrel contraceptive implants (N=32)
| Demographic/Characteristic | Median (Range) |
|---|---|
| Age (years) | 25.3 (18.3-37.2) |
| Body-mass index (kg/m2) | 25.5 (18.7-42.2) |
| Duration of implant use (months) | 24 (12-36) |
Table 2 contains medians and ranges for serum etonogestrel and topiramate concentrations during the course of the study. At baseline (Visit 1), participants had a median serum etonogestrel concentration of 142.0pg/mL (range 76.2-771.0). Participants had repeat median serum etonogestrel concentrations of 126.0pg/mL (range 72.4-585.0) at Visit 2, 119.0pg/mL (range 65.6-542.0) at Visit 3, and 105.0pg/mL (range 46.2-859.0) at Visit 4. Figure 2 demonstrates the box-plot distributions of serum etonogestrel concentrations at these time points. At Visit 2, median serum etonogestrel concentrations decreased by only 10.2% (range −86% to +215%) from baseline. By Visit 3, median serum etonogestrel concentrations had decreased by 20.1% (range −85% to +191%) from baseline. Finally, by Visit 4, median serum etonogestrel concentrations had decreased by 21.0% (range −88% to +215%). After converting median/ranges to mean/standard deviations, the 95% confidence interval (CI) for mean percent change in serum etonogestrel concentration was [−37.3%, +16.9%] for Visit 2, [−45.4%, +5.2%] for Visit 3, and [−66.8%, +24.8%] for Visit 4. Thus, the 95% CI’s for mean percent change in serum etonogestrel concentrations at all three visit timepoints crossed the −30% non-inferiority cut-off. Overall, 12.5% (8/32) of participants at Visit 2, 29.0% (9/31) at Visit 3, and 37.0% (10/27) at Visit 4 experienced a percent decrease in serum etonogestrel concentrations greater than the non-inferiority limit for this study.
Table 2:
Serum etonogestrel and serum topiramate concentrations before and during topiramate administration and titration
| Study Visit | Serum etonogestrel concentration (pg/mL) | Serum topiramate concentration (μg/mL) |
|---|---|---|
| All participants | ||
| Visit 1 (n=32) | 142.0 (76.2-771.0) | NA |
| Visit 2 (n=32) | 126.0 (72.4-585.0) | 2.4 (<1.5 – 4.0) |
| Visit 3 (n=31) | 119.0 (65.6-542.0) | 5.7 (<1.5 – 10.2) |
| Visit 4 (n=27) | 105.0 (46.2-859.0) | 9.3 (<1.5 – 13.1) |
| Therapeutic Participants * | ||
| Visit 1 (n=25) | 142.0 (99.8-771.0) | NA |
| Visit 2 (n=25) | 125.0 (72.4-217.0) | 2.6 (<1.5 – 3.9) |
| Visit 3 (n=25) | 119.0 (65.6-192.0) | 5.8 (3.8 – 10.2) |
| Visit 4 (n=22) | 95.0 (46.2-859.0) | 9.9 (2.1 – 13.1) |
| Non-therapeutic Participants * | ||
| Visit 1 (n=7) | 160.0 (76.2-335.0) | NA |
| Visit 2 (n=7) | 145.0 (75.5-585.0) | <1.5 (<1.5 – 4.0) |
| Visit 3 (n=6) | 176.0 (69.4-542.0) | <1.5 (<1.5 – 3.8) |
| Visit 4 (n=5) | 204.0 (68.3-408.0) | <1.5 (<1.5 – 3.3) |
Data are median (range)
Therapeutic defined as reaching a serum topiramate concentrations of ≥5.0μg/mL at any visit during the study
Figure 2:
Box plots of serum etonogestrel concentrations for all participants at each time point in the study. The box represents the first and third quartiles (IQRs [interquartile range]: 117.0–184.8, 95.3–162.0, 91.3–159.0, 83.1–150.0) with the band inside the box representing the median (142.0, 126.0, 119.0, 105.0). Whiskers represent the data within 1.5 IQR of the upper and lower quartile, or if no value exists within that range, then to the minimum or maximum values. Red dotted line marks the threshold for consistent ovulatory suppression (90 pg/mL). Outliers are represented by open circles (outside 1.5 times the IQR) and asterisks (outside 3 times the IQR).
Using a Friedman’s test for non-parametric, related samples, serum etonogestrel concentrations significantly decreased with increasing topiramate therapy (p<0.001). Serum etonogestrel concentrations steadily decreased with each up-titration in topiramate therapy and corresponding successive study visit. Only one participant at baseline (1/32 [3.1%], 95% CI 0.1%-16.2%) had a serum etonogestrel concentration <90pg/mL. Excluding the participant who had a serum etonogestrel concentration <90pg/mL at baseline, 30.8% of participants (8/26, 95% CI 14.3%-51.8%) had a serum etonogestrel concentration <90pg/mL at the maximum topiramate dose (Visit 4) (Table 3). Also excluding the same participant, 16.7% of participants (5/30, 95% CI 5.6%-34.7%) had a serum etonogestrel concentration <90pg/mL by Visit 3 (Table 4), and 9.7% of participants (3/31, 95% CI 2.0%-25.8%) had a serum etonogestrel concentration <90pg/mL by Visit 2 (Table 5).
Table 3:
Serum etonogestrel concentrations for contraceptive implant users that had a concentration <90pg/mL while taking topiramate 400mg per day
| Participant | Baseline (pg/mL) | Visit 2 (pg/mL) | Visit 3 (pg/mL) | Visit 4 (pg/mL) |
|---|---|---|---|---|
| Participant 21 | 99.8 | 83.9 | 65.6 | 46.2 |
| Participant 26 | 111.0 | 93.9 | 142.0 | 57.5 |
| Participant 31* | 76.2 | 75.5 | 69.4 | 68.3 |
| Participant 32 | 104.0 | 113.0 | 119.0 | 83.1 |
| Participant 35 | 142.0 | 115.0 | 119.0 | 81.9 |
| Participant 37 | 135.0 | 97.2 | 85.2 | 76.5 |
| Participant 39 | 102.0 | 93.0 | 86.9 | 80.6 |
| Participant 40 | 113.0 | 136.0 | 93.8 | 84.7 |
| Participant 48 | 771.0 | 108.0 | 113.0 | 89.3 |
This participant did not reach a therapeutic topiramate concentration (1.5 μg/mL [Visit 2] > 2.9 μg/mL [Visit 3] > 3.3μg/mL [Visit 4]).
All other participants reached therapeutic topiramate concentrations (>5.0μg/mL) during the study.
Table 4:
Serum etonogestrel concentrations for contraceptive implant users that had a concentration <90pg/mL while taking topiramate 200mg per day
| Participant | Baseline (pg/mL) | Visit 2 (pg/mL) | Visit 3 (pg/mL) | Visit 4 (pg/mL) |
|---|---|---|---|---|
| Participant 18 | 105.0 | 94.7 | 76.7 | 90.6 |
| Participant 21 | 99.8 | 83.9 | 65.6 | 46.2 |
| Participant 24* | 115.0 | 82.1 | 74.3 | † |
| Participant 31* | 76.2 | 75.5 | 69.4 | 68.3 |
| Participant 37 | 135.0 | 97.2 | 85.2 | 76.5 |
| Participant 39 | 102.0 | 93.0 | 86.9 | 80.6 |
Participant did not reach a therapeutic topiramate concentration during the study.
Participant discontinued from study prior to Visit 4.
All other participants reached therapeutic topiramate concentrations (>5.0μg/mL) during the study.
Table 5:
Serum etonogestrel concentrations for contraceptive implant users that had a concentration <90pg/mL while taking topiramate 100mg per day
| Participant | Baseline (pg/mL) | Visit 2 (pg/mL) | Visit 3 (pg/mL) | Visit 4 (pg/mL) |
|---|---|---|---|---|
| Participant 13 | 129.0 | 72.4 | 90.9 | † |
| Participant 21 | 99.8 | 83.9 | 65.6 | 46.2 |
| Participant 24* | 115.0 | 82.1 | 74.3 | † |
| Participant 31* | 76.2 | 75.5 | 69.4 | 68.3 |
Participant did not reach a therapeutic topiramate concentration during the study.
Participant discontinued from study prior to Visit 4.
All other participants reached therapeutic topiramate concentrations (>5.0μg/mL) during the study.
Using the standard cut-off of ≥5μg/mL for serum topiramate concentration, we found that 25 total participants reached a therapeutic serum topiramate level during the study (Table 2). All therapeutic participants completed Visits 2 and 3, with 22 therapeutic participants completing Visit 4. Therapeutic participants had similar median serum etonogestrel concentrations to all participants at each time point, except for Visit 4 where therapeutic participants had a median serum etonogestrel concentration of 95.0pg/mL (range 46.2-859) (Table 2). Figure 3 demonstrates the box-plot distributions of serum etonogestrel concentrations of only therapeutic participants. Using a Friedman’s test, we again found serum etonogestrel concentrations significantly decreased with increasing topiramate dose (p<0.001). Similar to our analysis of all participants, median serum etonogestrel concentrations for therapeutic participants steadily decreased with each up-titration in topiramate therapy. At visit 4, 36.4% (8/22) of therapeutic participants had a serum etonogestrel concentration <90pg/mL. The single non-therapeutic participant that had a serum etonogestrel concentration <90pg/mL at Visit 4 was the only participant who had a serum etonogestrel concentration <90pg/mL at baseline (Table 3).
Figure 3:
Box plots of serum etonogestrel concentrations for therapeutic participants at each time point in the study. Therapeutic participants are defined as those reaching a serum topiramate concentration of ≥5 microgram/mL during the study. The box represents the first and third quartiles (IQRs [interquartile range]; 118.0–177.5, 96.0–147.0, 92.6–138.0, 82.8–126.5) with the band inside the box representing the median (142.0, 125.0, 119.0, 95.0). Whiskers represent the data within 1.5 IQR of the upper and lower quartile, or if no value exists within that range, then to the minimum or maximum values. Red dotted line marks the threshold for consistent ovulatory suppression (90 pg/mL). Outliers are represented by open circles (outside 1.5 times the IQR). Extreme outliers (outside 3 times the IQR) excluded from the figure (participant 48 visit 1 [771 pg/mL] and participant 27 visit 4 [859 pg/mL]).
Discussion
In this pharmacokinetic drug-drug interaction study, we found that concomitant use of topiramate among etonogestrel implant users led to inferior serum etonogestrel concentrations based upon our pre-defined non-inferiority limit of 30%. Topiramate demonstrated a clear dose-dependent effect on serum etonogestrel concentrations causing an increasing number of etonogestrel implant users to experience decreases in serum etonogestrel concentrations beyond this non-inferiority limit. While we found minor decreases in etonogestrel concentrations at the standard dosage used for treatment of migraines (100mg per day), topiramate use at dosages for epileptic seizure prevention (>200mg per day) caused potentially clinically important reductions in serum etonogestrel concentrations among implant users. A significant proportion of participants had serum etonogestrel concentrations below the level needed to consistently suppress ovulation (90pg/mL) by the end of the study. The vast majority of participants (8/9) that had serum etonogestrel concentrations fall below this limit had therapeutic serum topiramate concentrations as well.
Our findings support that topiramate is a weak CYP3A EIAED based on standard FDA definitions for enzyme inducers (<50% average pharmacokinetic effect) (14). As compared to a moderate to strong CYP3A enzyme inducer like carbamazepine, concomitant topiramate use at seizure-preventing dosages resulted in a smaller percentage of participants experiencing a clinically significant decrease in serum etonogestrel concentrations below 90pg/mL (33% with topiramate versus 80% with carbamazepine) (8). However, we currently have no means to predict which contraceptive implant users will experience a clinically significant drug-drug interaction with topiramate. Research in the field of pharmacogenomics has demonstrated that individual genetic differences can affect both baseline exogenous steroid hormone metabolism and the degree to which enzyme inducing drugs influence this pharmacokinetic pathway (19–22). This research may eventually help health care professionals determine which hormonal contraceptive users are at the highest risk of CYP3A enzyme inducing interactions, but validation studies are needed to identify true genetic variants of interest that can be used to create personalized medicine tools. Until those tools are available, health care professionals should consider the dose of topiramate prescribed when counseling etonogestrel contraceptive implant users on this potential drug-drug interaction (6).
The primary limitation of our study is the focus on pharmacokinetic outcomes and not pharmacodynamic ones. Serum etonogestrel concentrations are a surrogate marker for increased risk of contraceptive failure, but we do not currently know the minimal serum etonogestrel concentration needed to maintain contraceptive efficacy through secondary mechanisms of action (e.g. cervical mucous thickening, delayed sperm transport) (12). Moderate to strong CYP3A enzyme inducers like carbamazepine and efavirenz have caused published contraceptive failures among etonogestrel implant users, but there are currently no published contraceptive implant failures with topiramate (9, 23). Given topiramate’s decreasing use as a primary treatment for epilepsy, most reproductive-aged females using topiramate are likely on much lower-dose regimens. Our findings indicate such “migraine dose” regimens pose a lower risk of decreasing etonogestrel concentrations but have enough of an effect to predispose to contraceptive failures (2). Our findings are also limited by the few outlier serum etonogestrel concentrations (>600pg/mL) of unknown cause that occurred during the course of the study. However, the use of non-parametric statistical tests for our primary analyses controls for these outliers and prevents them from having a disproportionate effect on our results. When determining duration of implant use, we relied upon participant self-report when date of implant insertion was not available in the electronic health record, data which could have been confounded by participant mis-recall. However, the use of a repeated measures study design utilizes each participant as their own control for comparison, and thus would account for any potential confounding by participant characteristics such as duration of implant use.
Our study is strengthened by the enrollment of etonogestrel contraceptive implant users, which have known relative steady-state pharmacokinetics after the first year of use and perfect drug compliance (12). We also incorporated serum topiramate concentrations as another measurement of compliance, which allowed us to perform a sub-group analysis with only participants reaching a therapeutic topiramate concentration. This methodology mirrors actual clinical practice when topiramate is prescribed as an anti-epileptic, thereby making our findings more generalizable to this patient population. Further, the repeated measures design of this study utilized each participant as their own control, which removes many potential confounders (e.g. BMI, duration of implant use).
In contrast to the prior drug-drug interaction studies with oral contraceptive pills and topiramate, we found a consistent, albeit weak enzyme inducing effect of topiramate on a systemic progestin (10, 11). Fortunately, given the dose dependent nature of this drug-drug interaction, contraceptive implant users prescribed topiramate for migraines likely face a much lower if any increased risk of contraceptive failure (2). Further, pertinent clinical outcome data (e.g. pregnancy rates) are needed to determine the true clinical significance of topiramate’s effect on serum etonogestrel concentrations. Ultimately, more data are needed on the drug-drug interaction between topiramate and different hormonal contraceptive formulations to determine if this interaction remains consistent across different progestins and leads to actual effects on contraceptive efficacy. Non-hormonal and local hormonal contraceptive methods, like the intrauterine devices, remain reliable contraceptive methods for individuals prescribed topiramate (6). Health care professionals should continue to counsel reproductive age female patients considering topiramate therapy on the teratogenicity of this drug and discuss the potential risk of a drug interaction with the etonogestrel contraceptive implant in a patient-centered fashion.
Supplementary Material
Authors’ Data Sharing Statement.
Will individual participant data be available (including data dictionaries)? No.
What data in particular will be shared? Not available.
What other documents will be available? Not available.
When will data be available (start and end dates)? Not applicable.
By what access criteria will data be shared (including with whom, for what types of analyses, and by what mechanism)? Not applicable.
Disclosure of Funding:
This study was primarily funded through an Investigator-Initiated Study grant from Merck Sharp & Dohme Corp [MISP#57073] to Dr. Teal. This work was also supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR001082. Dr. Lazorwitz’s time is supported by the NICHD K12 Women’s Reproductive Health Research Scholar Program (grant number 5K12HD001271-18). Contents are the authors’ sole responsibility and do not necessarily represent official NIH views. All funding sources listed had no involvement in the study design, collection, analysis, interpretation of data, writing of this report, or decision to submit this article for publication.
Financial Disclosure:
Dr. Teal serves on a Data Monitoring Board for a study funded by Merck and Co and has served as a consultant for Bayer Healthcare. The University of Colorado Department of Obstetrics and Gynecology has received research funding from Bayer, Agile Therapeutics, Sebela, and Medicines360. The other authors did not report any potential conflicts of interest.
The authors thank Judith Merritt, PhD at the Q Squared Solutions laboratory for assisting with the etonogestrel analysis for this study.
Footnotes
Each author has confirmed compliance with the journal’s requirements for authorship.
Presented at the 2021 Society of Family Planning Annual Meeting, held virtually, on October 1-2, 2021.
Clinical Trial Registration: ClinicalTrials.gov, NCT03335163.
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