Women with epilepsy or other nonepileptic neurologic conditions receiving antiepileptic drugs (AEDs) are often prescribed combination oral contraceptives (OCs) containing progesterone and estrogen (Doose et al., 2003; Penovich, 2004), both of which are metabolized by the cytochrome P450 (CYP) 3A system (Guengerich, 1988, 1990; Reddy, 2010). Approximately 17% of women with epilepsy, age 15–45 years, who are treated with an AED use combination OCs (Back & Orme, 1990; Shorvon et al., 2002; Sabers, 2008). AEDs with the potential to induce drug-metabolizing CYP enzymes (e.g., phenobarbital, carbamazepine, phenytoin, felbamate, topiramate, primidone, and oxcarbazepine) may cause a reduction in steroid contraceptive levels during concomitant administration, resulting in unplanned pregnancies (Crawford et al., 1990; Gatti et al., 2000; Wilbur & Ensom, 2000; Ragueneau-Majlessi et al., 2002; Reddy, 2010). Conversely, in some instances, OCs can alter the pharmacokinetic (PK) profile of AEDs (e.g., lamotrigine, valproic acid) and decrease their effectiveness in controlling seizures (Reddy, 2010).
Alternative or special contraceptive measures, including OCs with high estrogen content, have been recommended when using certain AEDs such as phenytoin, carbamazepine, and topiramate, since these agents have enzyme-inducing activity leading to reduced plasma steroid concentrations (Wilbur & Ensom, 2000; Doose et al., 2003; Reddy, 2010). Some newer AEDs such as gabapentin, levetiracetam, pregabalin, as well as vigabatrin, do not appear to possess significant CYP-inducing properties, and consequently, may not significantly alter the PK profile of concomitantly administered OCs (Bartoli et al., 1997; Eldon et al., 1998; Johannessen Landmark & Patsalos, 2010).
Lacosamide, is indicated as adjunctive therapy for adults with partial-onset seizures. It demonstrates linear PK properties with single doses of 100–800 mg or multiple doses of 200–500 mg administered twice daily, negligible first-pass metabolism, low plasma protein binding (≤15%) (Cawello et al., 2013; Fountain et al., 2012), a half-life of approximately 13 h, maximal concentrations in about 1–4 h following oral administration, and complete absorption with almost 100% bioavailability (Horstmann et al., 2002; Doty et al., 2007). Steady state plasma levels are achieved within 3 days of repeated oral administration (Horstmann et al., 2002).
Lacosamide and its major metabolite (an O-desmethyl metabolite) are eliminated primarily by the kidneys (Doty et al., 2007). The metabolism of lacosamide has not been fully characterized, but CYP2C19 and possibly CYP3A4 and CYP2C9 are involved in the formation of the O-desmethyl-metabolite (Cawello et al., 2010, 2012). Lacosamide did not induce or inhibit the activity of CYP isoenzymes at therapeutic concentrations, with the exception of potential inhibition of CYP2C19; however, an in vivo study with the CYP2C19 substrate omeprazole did not show an inhibitory effect on omeprazole pharmacokinetics (UCB, 2011). In other clinical studies, no PK interaction between lacosamide and carbamazepine, valproic acid, metformin, or digoxin was reported (Doty et al., 2007; Thomas et al., 2007; Cawello et al., 2010; Cawello & Bonn, 2012). A population PK analysis estimated that concomitant treatment with other AEDs known to be enzyme inducers (carbamazepine, phenytoin, phenobarbital, in various doses) decreased lacosamide plasma concentrations by 15–20% (UCB, 2011).
The present study assesses the effect of lacosamide on ovulation suppression by a combination OC containing ethinylestradiol, a synthetic estrogen, and levonorgestrel, a synthetic progesterone. A further objective was to evaluate the effect of lacosamide on the PK parameters of the OC and vice versa, and the tolerability of coadministration of the medications.
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This study was carried out in accordance with the relevant International Conference on Harmonisation (ICH)-guidelines, Good Clinical Practice (GCP), the regulations of the German Drug Law, and the principles described in the Declaration of Helsinki, revision of Edinburgh, Scotland (October 2000). An independent ethics committee (IEC) at the Chamber of Physicians, Berlin (Ärztekammer, Berlin) and at the Chamber of Physicians, Brandenburg (Ärztekammer, Brandenburg) reviewed and approved the protocol and its amendments and informed consent forms. The IEC provided ongoing review of the clinical trial.
This study included 40 premenopausal nonpregnant Caucasian women 18–40 years of age who were eligible if they weighed between 50 and 100 kg (body mass index [BMI] 20–30 kg/m2), were considered to be in good health as determined by medical history, physical examination, vital signs, 12-lead electrocardiography (ECG), and clinical laboratory findings, were nonsmokers, and had negative blood tests for human immunodeficiency virus, hepatitis B, hepatitis C, and negative alcohol (breath test) and drug tests (urinalysis). Women were excluded if they had undergone hysterectomy or ovariectomy; did not agree to use a barrier method of contraception; were pregnant or breastfeeding; had any clinically significant laboratory, medical, or psychiatric disturbance likely to jeopardize the volunteer's ability to participate in the study; received any medication within 2 weeks of first day of dosing with test substance, had received an investigational medication within the past 3 months; had a history of chronic alcohol or drug abuse within past 6 months; or had a serious medical condition. Written informed consent was obtained prior to performing the trial eligibility assessments.
This was an open-label, one-arm trial with a duration of approximately 90 days (Fig. 1). Eligible women entered cycle 1 of the study on the first day of menstruation. Cycle 1 was a medication-free, run-in phase of approximately 28 days to confirm that normal ovulation occurred. Serum progesterone was measured 7 days before the expected onset of menstruation (approximately day 21 of cycle 1). Women not ovulating during cycle 1 were excluded from the remainder of the trial.
Figure 1. Trial design. Only volunteers with confirmed ovulation in cycle 1 were eligible to enter cycle 2, and only volunteers with confirmed suppression of ovulation were eligible to enter cycle 3. All PK and PD evaluations took place during cycle 3. D, day; LCM, lacosamide; OC, oral contraceptive (0.03 mg ethinylestradiol plus 0.15 mg levonorgestrel).
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Ovulating women who completed cycle 1 received the OC containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel (Microgynon; Schering AG, Berlin, Germany) once daily for the first 21 days of cycle 2. On day 21, the ovulation status of each volunteer was determined by the measurement of serum progesterone. Those who ovulated during cycle 2 were excluded from the remainder of the trial. A 24-h PK profile of the OC components was assessed on day 12.
Cycle 3 evaluated potential pharmacodynamic (PD) and PK interactions between lacosamide (Vimpat; UCB Pharma, Monheim, Germany) and the OC. Volunteers received the OC for the first 21 days of cycle 3, lacosamide 400 mg/day (200 mg twice daily) for 9 days from days 3 to 11, and a single morning dose of lacosamide 200 mg on day 12. On day 12, the 24-h PK profile of ethinylestradiol and levonorgestrel was evaluated, and from days 12 to 15 the 72-h PK profile of lacosamide. On day 21, ovulation was determined by measuring serum progesterone.
On day 1 of each cycle, volunteers received a diary to document intake of concomitant medication and any adverse event (AE). Pregnancy screening based on measurement of the β subunit of human chorionic gonadotropin (β-HCG) in serum was conducted during the screening cycle, 7 days prior to the expected onset of cycle 2, and days 1 and 22 of cycle 3 (post study follow-up).
Volunteers stayed in the study center (3C Clinical Research Unit ar Charité University Hospital; Berlin, Germany) for 12 h on day 12 (PK profiling day) of cycle 2 and on days 3–13 of cycle 3. On days 1–21 of cycles 2 and 3 volunteers were asked to take their OC at the study clinic; if logistically not possible, they could take it at home, but were required to return to the clinic for a single day between days 9 and 11 of cycle 3 for blood sampling for lacosamide PK assessment. While in the clinic, volunteers fasted overnight and had breakfast 1 h after dosing on days 3–11 of cycle 3. On PK profiling days (day 12 of cycles 2 and 3), no breakfast was given, and lunch, snack, and dinner were served at approximately 4, 8, and 10 h, respectively, post dose.
The consumption of food and beverages containing caffeine, grapefruit juice, and quinine was not allowed within 24 h of screening, day 1 and days 11–13 of cycle 2, days 2–15 of cycle 3, and day 21 of cycles 1–3. Volunteers were also asked to refrain from alcohol consumption within 24 h of screening and from 24 h before check-in (day 3 of cycle 3) up to the end of the experimental parts of the study.
Successful ovulation suppression was defined as a serum progesterone concentration of <5.1 nm on day 21 of cycle 2, when volunteers received OC alone, and on day 21 of cycle 3, when they received concomitant lacosamide 400 mg/day and OC. Unfrozen blood samples (1.1 ml) were sent to the analytical laboratory (Gesellschaft mbH für Labortechnologie in Wissenschaft und Technik, Berlin, Germany), and progesterone levels were measured by radioimmunoassay as soon as possible. Frozen aliquots were stored after analysis.
For the PK analyses, at least 9 ml (ethinylestradiol and levonorgestrel assessment) or 4.9 ml (lacosamide assessment) of blood was collected into glass lithium heparin tubes at each sample collection time point. Within 30 min, the samples were centrifuged (~1,500 g) for 10 min at 4°C. Plasma was separated and transferred into two glass tubes and stored at −20°C or less until assayed at the bioanalytical lab (NUVISAN, Neu-Ulm, Germany). Ethinylestradiol and levonorgestrel were analyzed by gas chromatography/mass spectrometry (GC/MS) with a lower limit of quantification (LLOQ) of 10 pg/ml and 0.25 ng/ml, respectively. Lacosamide was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the LLOQ was 0.1 μg/ml.
Ethinylestradiol and levonorgestrel
Plasma concentration-time curves for ethinylestradiol and levonorgestrel (24 h) were assessed on day 12 of cycle 2. On day 12, blood sampling for measuring the PK parameters was performed before, and at the following intervals after OC dosing: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h. Predose samples were also taken on days 1 (blank) and 21. During cycle 3, blood samples were obtained on days 1 (predose blank sample), 12, and 21 (predose). On day 12, blood samples were collected predose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h after OC dosing.
The PK parameters derived from the individual concentration-time curves of ethinylestradiol and levonorgestrel (24-h profiles on day 12 in cycles 2 and 3) included the area under the plasma concentration versus time curve at steady state during a dosing interval (AUC0-24 h,ss), calculated using the log/linear trapezoidal method, the maximum steady-state plasma drug concentration (Cmax,ss), and tmax,ss, the time to reach Cmax,ss.
Plasma concentration-time curves for lacosamide (72 h) were assessed beginning on day 12 of cycle 3. On day 12, blood samples were obtained predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, and 72 h postdose. Predose samples were also obtained on day 3 (blank) and before the morning dose of lacosamide on a selected day between days 9 and 11. PK parameters derived from the individual concentration-time curves of lacosamide (72-h profiles beginning on day 12 of cycle 3) included AUC0-12 h,ss, Cmax,ss, and tmax,ss.
Tolerability and safety
Volunteers were monitored for AEs during the entire trial. AEs were graded by degree of seriousness and intensity, estimated for causality, and assessed for outcome. Clinical laboratory parameters (including hematology, biochemistry, and urinalysis), vital signs (blood pressure, pulse, body temperature), and 12-lead ECG recordings were assessed at the eligibility visit, day 1 (predose OC) and day 21 of cycle 2, day 3 (predose lacosamide) and day 13 of cycle 3, and at follow-up (day 22 of cycle 3).
Statistical analyses were performed using SAS Version 6.12 (SAS Institute Inc., Cary, NC, U.S.A.). Only data for volunteers who entered cycle 2 were evaluated. Descriptive statistics were used for continuous variables. Ovulation suppression was analyzed as a categorical variable, and the 90% confidence intervals (CIs) for the percentage of volunteers with successful suppression of ovulation were calculated separately for cycles 2 and 3 according to Clopper & Pearson (1934). Progesterone concentrations were summarized by descriptive statistics and 90% CIs for differences between cycles 2 and 3.
PK data were summarized with descriptive statistics. Noncompartmental PK parameters were derived from the individual concentration-time curves of ethinylestradiol and levonorgestrel (24-h profiles of day 12 in cycles 2 and 3). For lacosamide, noncompartmental PK parameters were derived from the 72-h profile, beginning predose on day 12 in cycle 3. Unless otherwise stated, all values are presented as mean ± standard deviation.
Safety variables were summarized for all volunteers who entered cycle 2. AEs were summarized by cycle and stratified by AEs starting prior to and those starting or worsening after first lacosamide dose administered concomitantly with OC.
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In this open-label trial in healthy females, lacosamide 400 mg/day did not affect ovulation suppression by an OC (ethinylestradiol plus levonorgestrel) as confirmed by serum progesterone levels. In each of the 31 women who completed the trial, serum progesterone concentration did not exceed 5.1 nm on day 21 of cycle 3 (lacosamide plus OC), the criterion for successful ovulation suppression. Although there was a slight increase in serum progesterone levels when lacosamide was coadministered with the OC, the upper limit of the 90% CI remained well below the 5.1 nm threshold.
The PK parameters of the OC components measured with and without lacosamide coadministration were almost all within the bioequivalence range, indicating that lacosamide did not significantly affect the PK profile of the OC. There was a tendency for increased AUC0-24,ss and Cmax,ss for both ethinylestradiol and levonorgestrel during lacosamide coadministration; however, with the exception of the point estimate and 90% CIs for ethinylestradiol for Cmax,ss (1.205, 1.106–1.312), the remaining point estimates and 90% CIs for the AUC0-24,ss and Cmax,ss ratios for ethinylestradiol and levonorgestrel were entirely contained within the acceptance range of 80–125%. The increase in ethinylestradiol Cmax,ss is not considered clinically relevant.
The PK characteristics of lacosamide when taken concurrently with the OC (AUC of 113.5 ± 20.7 μg h/ml, Cmax of 13.8 ± 2.2 μg/ml, tmax of 1.1 ± 0.4 h, t½ of 15.3 ± 2.0) were consistent with those reported earlier for lacosamide alone (with adaptation for the ~30% difference in body weight): AUC of 79.7 ± 13.4 and 82.7 ± 13.9 μg h/ml, Cmax of 9.1 ± 1.6 μg/ml, tmax of 2.4 ± 1.0, and 0.5 (0.5–1.0) h (Cawello et al., 2010; Cawello & Bonn, 2012), and t½ of approximately 13 h (Horstmann et al., 2002; Hovinga, 2003; Bialer et al., 2007), indicating that the OC did not alter the PK profile of lacosamide. These results suggest that concomitant administration of lacosamide and OCs will not affect the anticonvulsant properties of lacosamide.
No serious AEs occurred during this trial. A greater number of AEs—including skin-related reactions, tiredness, dizziness, and paresthesia of the mouth—were reported during coadministration of lacosamide and the OC compared with treatment with the OC alone; however, these were mild or moderate in intensity and none led to study withdrawal. No clinically relevant changes in clinical laboratory values, cardiovascular, or ECG parameters were observed during coadministration of lacosamide and the OCs.
The limitation of this trial is that only the PK and PD interactions of lacosamide with the ethinylestradiol plus levonorgestrel combination OC were evaluated. Therefore, the extent to which the results are applicable to women with epilepsy who may be using different OCs or may be taking additional concomitant AEDs is not known.
In conclusion, coadministration of the ethinylestradiol plus levonorgestrel combination OC with lacosamide was generally well tolerated and did not appear to result in clinically meaningful PD or PK interactions. These results suggest that the ethinylestradiol plus levonorgestrel combination OCs can be used in patients receiving lacosamide without the risk of contraceptive failure or loss of seizure control.
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This study was funded by UCB Pharma. The cooperation and contribution made by the volunteers and their families is gratefully recognized. The clinical study, as well the statistical analysis, was performed by PAREXEL International GmbH, Berlin, Germany. Laboratory services were provided by Dr. H. Tabel and Dr. T. Wurche, Gesellschaft mbH für Labortechnologie in Wissenschaft und Technik, Berlin, Germany, and measurements of drug concentrations in plasma were performed by NUVISAN GmbH, Neu-Ulm, Germany. Merrilee Johnstone, PhD, from Prescott Medical Communications Group (Chicago, IL) as well as Azita Tofighy, PhD, from UCB Pharma (Brussels, Belgium) provided writing assistance.