Epilepsia, 54(3):530–536, 2013

doi: 10.1111/epi.12085

FULL-LENGTH ORIGINAL RESEARCH

Pharmacodynamic and pharmacokinetic evaluation of

coadministration of lacosamide and an oral contraceptive
(levonorgestrel plus ethinylestradiol) in healthy female
volunteers
*Willi Cawello, †Bernd Rosenkranz, ‡Bernhard Schmid, and §Werner Wierich

*UCB Pharma, Monheim am Rhein, Germany; †Division of Pharmacology, University of Stellenbosch, Tygerberg, Cape Town,
South Africa; ‡NUVISAN GmbH, Neu-Ulm, Germany; and §Berlin, Germany

samide was administered concomitantly. The AUC of

SUMMARY
ethinylestradiol alone versus together with lacosamide
Purpose: To determine whether the antiepileptic drug was 1,067  404 versus 1,173  330 pg h/ml. Corre-
lacosamide affects the pharmacokinetics or pharmaco- sponding values of Cmax were 116.9  48.8 versus
dynamics of a combined oral contraceptive (OC; ethiny- 135.7  28.6 pg/ml. For levonorgestrel, the AUC alone
lestradiol 0.03 mg plus levonorgestrel 0.15 mg). was 74.2  21.4 versus 80.9  18.5 ng h/ml with lacosa-
Methods: This was an open-label trial in healthy female mide. Corresponding values of Cmax were 6.7  1.9 versus
volunteers. Eligible women entered cycle 1 of the trial on 7.4  1.5 ng/ml. The AUC and Cmax point estimates and
the first day of menstruation. Cycle 1 was a medication- almost all 90% confidence intervals (except for Cmax of
free, run-in phase of approximately 28 days to confirm ethinylestradiol) for ethinylestradiol and levonorgestrel
that normal ovulation occurred. Volunteers with con- (with and without lacosamide) were within the conven-
firmed ovulation entered the subsequent cycle and tional bioequivalence range, and no relevant changes in
started taking OCs. After establishing ovulation suppres- tmax were observed for ethinylestradiol (1.5  0.6 h alone
sion (defined as progesterone serum concentration vs. 1.4  0.7 h with lacosamide) or for levonorgestrel
<5.1 nM on day 21 of the menstrual cycle) in volunteers (1.5  1.0 h alone vs. 1.1  0.6 h with lacosamide).
taking the OCs in cycle 2, lacosamide 400 mg/day was Lacosamide pharmacokinetics were consistent with those
administered concomitantly in the subsequent cycle observed in previous studies of lacosamide alone,
(cycle 3). The pharmacokinetic parameters of area under with values for AUC of 113.5  20.7 lg h/ml, Cmax of
the concentration-time curve (AUC), maximum steady- 13.8  2.2 lg/ml, and tmax of 1.1  0.4 h.
state plasma drug concentration (Cmax), and time to max- Significance: Lacosamide and an OC containing ethiny-
imum concentration (tmax) were measured for the OC lestradiol and levonorgestrel have low potential for drug–
components and lacosamide. drug interaction; therefore, coadministration of the two
Key Findings: A total of 37 volunteers completed cycle 1, drugs is unlikely to result in contraceptive failure or loss of
and 32 completed cycle 2. In each of the 31 volunteers seizure control.
who completed the trial (through cycle 3), pharmacody- KEY WORDS: Lacosamide, Oral contraceptive, Epilepsy,
namic assessment showed progesterone serum concen- Drug–drug interaction, Pharmacokinetics, Pharmacody-
tration was <5.1 nM on day 21 of cycle 2, when the OC was namics.
administered alone, and on day 21 of cycle 3, when laco-

Women with epilepsy or other nonepileptic neurologic cytochrome P450 (CYP) 3A system (Guengerich, 1988,
conditions receiving antiepileptic drugs (AEDs) are often 1990; Reddy, 2010). Approximately 17% of women with
prescribed combination oral contraceptives (OCs) con- epilepsy, age 15–45 years, who are treated with an AED use
taining progesterone and estrogen (Doose et al., 2003; combination OCs (Back & Orme, 1990; Shorvon et al.,
Penovich, 2004), both of which are metabolized by the 2002; Sabers, 2008). AEDs with the potential to induce
drug-metabolizing CYP enzymes (e.g., phenobarbital, car-
Accepted November 27, 2012; Early View publication January 29, 2013. bamazepine, phenytoin, felbamate, topiramate, primidone,
Address correspondence to Willi Cawello, UCB Pharma, Global Biosta-
tistics, Alfred Nobel Strasse 10, D-40789 Monheim am Rhein, Germany.
and oxcarbazepine) may cause a reduction in steroid contra-
E-mail: willi.cawello@ucb.com ceptive levels during concomitant administration, resulting
Wiley Periodicals, Inc. in unplanned pregnancies (Crawford et al., 1990; Gatti
© 2013 International League Against Epilepsy et al., 2000; Wilbur & Ensom, 2000; Ragueneau-Majlessi

530
 531
Lacosamide with an Oral Contraceptive

et al., 2002; Reddy, 2010). Conversely, in some instances,

OCs can alter the pharmacokinetic (PK) profile of AEDs
Methods
(e.g., lamotrigine, valproic acid) and decrease their effec- This study was carried out in accordance with the relevant
tiveness in controlling seizures (Reddy, 2010). International Conference on Harmonisation (ICH)-guide-
Alternative or special contraceptive measures, including lines, Good Clinical Practice (GCP), the regulations of the
OCs with high estrogen content, have been recommended German Drug Law, and the principles described in the
when using certain AEDs such as phenytoin, carbamaz- Declaration of Helsinki, revision of Edinburgh, Scotland
epine, and topiramate, since these agents have enzyme- (October 2000). An independent ethics committee (IEC) at
inducing activity leading to reduced plasma steroid €
the Chamber of Physicians, Berlin (Arztekammer, Berlin)
concentrations (Wilbur & Ensom, 2000; Doose et al., 2003; €
and at the Chamber of Physicians, Brandenburg (Arztekam-
Reddy, 2010). Some newer AEDs such as gabapentin, mer, Brandenburg) reviewed and approved the protocol and
levetiracetam, pregabalin, as well as vigabatrin, do not its amendments and informed consent forms. The IEC
appear to possess significant CYP-inducing properties, and provided ongoing review of the clinical trial.
consequently, may not significantly alter the PK profile of
concomitantly administered OCs (Bartoli et al., 1997; Study participants
Eldon et al., 1998; Johannessen Landmark & Patsalos, 2010). This study included 40 premenopausal nonpregnant Cau-
Lacosamide, is indicated as adjunctive therapy for adults casian women 18–40 years of age who were eligible if they
with partial-onset seizures. It demonstrates linear PK prop- weighed between 50 and 100 kg (body mass index [BMI]
erties with single doses of 100–800 mg or multiple doses of 20–30 kg/m2), were considered to be in good health as
200–500 mg administered twice daily, negligible first-pass determined by medical history, physical examination, vital
metabolism, low plasma protein binding (  15%) (Cawello signs, 12-lead electrocardiography (ECG), and clinical lab-
et al., 2013; Fountain et al., 2012), a half-life of approxi- oratory findings, were nonsmokers, and had negative blood
mately 13 h, maximal concentrations in about 1–4 h tests for human immunodeficiency virus, hepatitis B, hepa-
following oral administration, and complete absorption with titis C, and negative alcohol (breath test) and drug tests
almost 100% bioavailability (Horstmann et al., 2002; Doty (urinalysis). Women were excluded if they had undergone
et al., 2007). Steady state plasma levels are achieved within hysterectomy or ovariectomy; did not agree to use a barrier
3 days of repeated oral administration (Horstmann et al., method of contraception; were pregnant or breastfeeding;
2002). had any clinically significant laboratory, medical, or psychi-
Lacosamide and its major metabolite (an O-desmethyl atric disturbance likely to jeopardize the volunteer’s ability
metabolite) are eliminated primarily by the kidneys (Doty to participate in the study; received any medication within
et al., 2007). The metabolism of lacosamide has not been 2 weeks of first day of dosing with test substance, had
fully characterized, but CYP2C19 and possibly CYP3A4 received an investigational medication within the past
and CYP2C9 are involved in the formation of the 3 months; had a history of chronic alcohol or drug abuse
O-desmethyl-metabolite (Cawello et al., 2010, 2012). within past 6 months; or had a serious medical condition.
Lacosamide did not induce or inhibit the activity of CYP Written informed consent was obtained prior to performing
isoenzymes at therapeutic concentrations, with the excep- the trial eligibility assessments.
tion of potential inhibition of CYP2C19; however, an in
vivo study with the CYP2C19 substrate omeprazole did Trial design
not show an inhibitory effect on omeprazole pharmaco- This was an open-label, one-arm trial with a duration of
kinetics (UCB, 2011). In other clinical studies, no PK inter- approximately 90 days (Fig. 1). Eligible women entered
action between lacosamide and carbamazepine, valproic cycle 1 of the study on the first day of menstruation. Cycle 1
acid, metformin, or digoxin was reported (Doty et al., was a medication-free, run-in phase of approximately
2007; Thomas et al., 2007; Cawello et al., 2010; Cawello 28 days to confirm that normal ovulation occurred. Serum
& Bonn, 2012). A population PK analysis estimated that progesterone was measured 7 days before the expected
concomitant treatment with other AEDs known to be onset of menstruation (approximately day 21 of cycle 1).
enzyme inducers (carbamazepine, phenytoin, phenobarbi- Women not ovulating during cycle 1 were excluded from
tal, in various doses) decreased lacosamide plasma con- the remainder of the trial.
centrations by 15–20% (UCB, 2011). Ovulating women who completed cycle 1 received the OC
The present study assesses the effect of lacosamide containing 0.03 mg ethinylestradiol and 0.15 mg levonorge-
on ovulation suppression by a combination OC containing strel (Microgynon; Schering AG, Berlin, Germany) once
ethinylestradiol, a synthetic estrogen, and levonorgestrel, a daily for the first 21 days of cycle 2. On day 21, the ovulation
synthetic progesterone. A further objective was to evaluate status of each volunteer was determined by the measurement
the effect of lacosamide on the PK parameters of the OC of serum progesterone. Those who ovulated during cycle 2
and vice versa, and the tolerability of coadministration of were excluded from the remainder of the trial. A 24-h PK pro-
the medications. file of the OC components was assessed on day 12.

Epilepsia, 54(3):530–536, 2013

doi: 10.1111/epi.12085
532
W. Cawello et al.

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).
Epilepsia ILAE

Cycle 3 evaluated potential pharmacodynamic (PD) and when volunteers received OC alone, and on day 21 of cycle
PK interactions between lacosamide (Vimpat; UCB 3, when they received concomitant lacosamide 400 mg/day
Pharma, Monheim, Germany) and the OC. Volunteers and OC. Unfrozen blood samples (1.1 ml) were sent to the
received the OC for the first 21 days of cycle 3, lacosamide analytical laboratory (Gesellschaft mbH f€ur Labortechnolo-
400 mg/day (200 mg twice daily) for 9 days from days 3 to gie in Wissenschaft und Technik, Berlin, Germany), and
11, and a single morning dose of lacosamide 200 mg on day progesterone levels were measured by radioimmunoassay as
12. On day 12, the 24-h PK profile of ethinylestradiol and soon as possible. Frozen aliquots were stored after analysis.
levonorgestrel was evaluated, and from days 12 to 15 the
72-h PK profile of lacosamide. On day 21, ovulation was Pharmacokinetic assessment
determined by measuring serum progesterone. For the PK analyses, at least 9 ml (ethinylestradiol and
On day 1 of each cycle, volunteers received a diary to levonorgestrel assessment) or 4.9 ml (lacosamide assess-
document intake of concomitant medication and any ment) of blood was collected into glass lithium heparin
adverse event (AE). Pregnancy screening based on measure- tubes at each sample collection time point. Within 30 min,
ment of the b subunit of human chorionic gonadotropin the samples were centrifuged (~1,500 g) for 10 min at 4°C.
(b-HCG) in serum was conducted during the screening Plasma was separated and transferred into two glass tubes
cycle, 7 days prior to the expected onset of cycle 2, and days and stored at 20°C or less until assayed at the bioanalytical
1 and 22 of cycle 3 (post study follow-up). lab (NUVISAN, Neu-Ulm, Germany). Ethinylestradiol and
Volunteers stayed in the study center (3C Clinical levonorgestrel were analyzed by gas chromatography/mass
Research Unit ar Charité University Hospital; Berlin, spectrometry (GC/MS) with a lower limit of quantification
Germany) for 12 h on day 12 (PK profiling day) of cycle 2 (LLOQ) of 10 pg/ml and 0.25 ng/ml, respectively. Laco-
and on days 3–13 of cycle 3. On days 1–21 of cycles 2 and 3 samide was analyzed by liquid chromatography-tandem
volunteers were asked to take their OC at the study clinic; if mass spectrometry (LC-MS/MS), and the LLOQ was
logistically not possible, they could take it at home, but were 0.1 lg/ml.
required to return to the clinic for a single day between days
9 and 11 of cycle 3 for blood sampling for lacosamide PK Ethinylestradiol and levonorgestrel
assessment. While in the clinic, volunteers fasted overnight Plasma concentration-time curves for ethinylestradiol
and had breakfast 1 h after dosing on days 3–11 of cycle 3. and levonorgestrel (24 h) were assessed on day 12 of cycle
On PK profiling days (day 12 of cycles 2 and 3), no break- 2. On day 12, blood sampling for measuring the PK parame-
fast was given, and lunch, snack, and dinner were served at ters was performed before, and at the following intervals
approximately 4, 8, and 10 h, respectively, post dose. after OC dosing: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 h.
The consumption of food and beverages containing caf- Predose samples were also taken on days 1 (blank) and 21.
feine, grapefruit juice, and quinine was not allowed within During cycle 3, blood samples were obtained on days 1 (pre-
24 h of screening, day 1 and days 11–13 of cycle 2, days dose blank sample), 12, and 21 (predose). On day 12, blood
2–15 of cycle 3, and day 21 of cycles 1–3. Volunteers were samples were collected predose, and at 0.5, 1, 1.5, 2, 3, 4, 6,
also asked to refrain from alcohol consumption within 24 h 8, 10, 12, and 24 h after OC dosing.
of screening and from 24 h before check-in (day 3 of cycle The PK parameters derived from the individual concen-
3) up to the end of the experimental parts of the study. tration-time curves of ethinylestradiol and levonorgestrel
(24-h profiles on day 12 in cycles 2 and 3) included the area
Pharmacodynamic assessment under the plasma concentration versus time curve at steady
Successful ovulation suppression was defined as a serum state during a dosing interval (AUC0-24 h,ss), calculated
progesterone concentration of <5.1 nM on day 21 of cycle 2, using the log/linear trapezoidal method, the maximum

Epilepsia, 54(3):530–536, 2013

doi: 10.1111/epi.12085
 533
Lacosamide with an Oral Contraceptive

steady-state plasma drug concentration (Cmax,ss), and tmax,ss, For lacosamide, noncompartmental PK parameters were
the time to reach Cmax,ss. derived from the 72-h profile, beginning predose on day 12
in cycle 3. Unless otherwise stated, all values are presented
Lacosamide as mean  standard deviation.
Plasma concentration-time curves for lacosamide (72 h) Safety variables were summarized for all volunteers who
were assessed beginning on day 12 of cycle 3. On day 12, entered cycle 2. AEs were summarized by cycle and strati-
blood samples were obtained predose and at 0.5, 1, 1.5, 2, 3, fied by AEs starting prior to and those starting or worsening
4, 6, 8, 10, 12, 24, 48, and 72 h postdose. Predose samples after first lacosamide dose administered concomitantly with
were also obtained on day 3 (blank) and before the morning OC.
dose of lacosamide on a selected day between days 9
and 11. PK parameters derived from the individual concen-
tration-time curves of lacosamide (72-h profiles beginning
Results
on day 12 of cycle 3) included AUC0-12 h,ss, Cmax,ss, Study participants
and tmax,ss. Of the 40 volunteers enrolled, 37 completed cycle 1, 32
completed cycle 2, and 31 completed the trial as scheduled;
Tolerability and safety nine volunteers withdrew. Of the nine women who with-
Volunteers were monitored for AEs during the entire drew, three had no ovulation during cycle 1, 2 withdrew
trial. AEs were graded by degree of seriousness and inten- their consent, two were noncompliant, and two withdrew
sity, estimated for causality, and assessed for outcome. Clin- due to AEs. Volunteers who entered cycle 2 (n = 37) had a
ical laboratory parameters (including hematology, mean (SD) age of 30.5 (5.3) years, and a height, weight, and
biochemistry, and urinalysis), vital signs (blood pressure, body mass index (BMI) of 169.5 (6.5) cm, 63.65 (7.26) kg,
pulse, body temperature), and 12-lead ECG recordings were and 22.12 (1.83) kg/m2, respectively.
assessed at the eligibility visit, day 1 (predose OC) and day
21 of cycle 2, day 3 (predose lacosamide) and day 13 of Primary outcome (pharmacodynamics)
cycle 3, and at follow-up (day 22 of cycle 3). The primary objective of this trial was to ascertain the
effect of lacosamide on the suppression of ovulation by
Statistical evaluation the OC as assessed by measuring progesterone serum con-
Statistical analyses were performed using SAS Version centration. In the 31 volunteers who completed the trial
6.12 (SAS Institute Inc., Cary, NC, U.S.A.). Only data for according to protocol, serum progesterone concentration
volunteers who entered cycle 2 were evaluated. Descriptive on day 21 ranged from 0.2 to 2.3 nM in both cycle 2 (OC
statistics were used for continuous variables. Ovulation sup- alone) and cycle 3 (lacosamide plus OC) (Table 1).
pression was analyzed as a categorical variable, and the Because serum progesterone level remained <5.1 nM on
90% confidence intervals (CIs) for the percentage of volun- both test dates, the predefined criterion for successful sup-
teers with successful suppression of ovulation were calcu- pression of ovulation was considered to have been met.
lated separately for cycles 2 and 3 according to Clopper & Although there was a slight increase of 0.21 nM in mean
Pearson (1934). Progesterone concentrations were summa- serum progesterone level from cycle 2 (OC alone) to
rized by descriptive statistics and 90% CIs for differences cycle 3 (lacosamide plus OC) (Table 1), the maximum
between cycles 2 and 3. level was the same for each cycle (2.3 nM) and still well
PK data were summarized with descriptive statistics. below 5.1 nM, indicating that lacosamide did not alter the
Noncompartmental PK parameters were derived from the PD effect of the OCs. Serum progesterone levels in cycle
individual concentration-time curves of ethinylestradiol and 1 (no medication) confirmed normal ovulation prior to the
levonorgestrel (24-h profiles of day 12 in cycles 2 and 3). administration of OCs (Table 1).

Table 1. Progesterone levels by cycle in volunteers who completed all three cycles (n = 31)
P4 levels in serum (nM) on day 21
Cycle 1 Cycle 2 Cycle 3 DP4
No medication OC alone LCM plus OC cycles 2 and 3 (nM)
Mean  SD 35.81  13.09 0.93  0.58 1.14  0.55 0.21  0.68
90% CI 31.00–40.60 0.71–1.14 0.93–1.33 0.00–0.41
Minimum 5.5 0.2 0.2 1.3
Maximum 57.0 2.3 2.3 1.6
Median 38.78 0.92 1.18 0.13
LCM, lacosamide; P4, progesterone; OC, oral contraceptive (0.03 mg ethinylestradiol plus 0.15 mg levonorgestrel).

Epilepsia, 54(3):530–536, 2013

doi: 10.1111/epi.12085
534
W. Cawello et al.

Figure 2.
Mean plasma concentration of ethinylestradiol (A) and levonorgestrel (B) with and without coadministration of lacosamide. Results
include all volunteers who completed cycle 3 (n = 31).
Epilepsia ILAE

Pharmacokinetic outcomes The PK characteristics of lacosamide when taken concur-

The PK profile of ethinylestradiol and levonorgestrel in rently with the OCs (Table 2) were consistent with the
cycle 2 was evaluated in the 36 volunteers who took the known PK profile of lacosamide alone (Horstmann et al.,
OCs from day 1 to day 21. In cycle 3, 31 volunteers took the 2002; Hovinga, 2003; Bialer et al., 2007; Cawello et al.,
OCs from day 1 to day 21 and contributed data for the PK 2010).
analyses of the OC components and lacosamide. The 24-h
plasma concentration-time curves for ethinylestradiol and Safety outcomes
levonorgestrel on day 12 of cycle 2 (OC alone) and cycle 3 During coadministration of OCs and lacosamide, no
(lacosamide plus OC) were similar with or without the pres- serious AEs were observed. Of the 40 enrolled partici-
ence of lacosamide (Fig. 2). The PK parameters of ethiny- pants, 37 reported 288 AEs. Two of the nine volunteers
lestradiol and levonorgestrel were similar in cycles 2 and 3 who withdrew from the study, did so as a result of AEs—
(Table 2), with a slight increase in AUC0-24 h,ss and Cmax,ss 1 due to fever and infection in cycle 1, and one due to an
for both OC components during co-administration of elevated eosinophil count on day 1 of cycle 2 before coad-
lacosamide compared with treatment with OC alone. All ministration of lacosamide. Of the 288 events 228 (79%)
differences and their 90% confidence intervals were within were mild and 59 (20.5%) events were of moderate inten-
the conventional bioequivalence range (80–125%), except sity. Only one event (acute bronchitis) experienced by one
for Cmax,ss of ethinylestradiol, where the upper limit of the volunteer on day 6 of cycle 2 was considered by the
CI was slightly above 125%. investigator as severe.

Epilepsia, 54(3):530–536, 2013

doi: 10.1111/epi.12085
 535
Lacosamide with an Oral Contraceptive

Although there was a slight increase in serum progesterone

Table 2. Pharmacokinetic parameters of
levels when lacosamide was coadministered with the OC,
ethinylestradiol and levonorgestrel on day 12 of cycle 2
(alone) and cycle 3 (with lacosamide), and lacosamide on the upper limit of the 90% CI remained well below the
day 12 of cycle 3 (with ethinylestradiol and 5.1 nM threshold.
levonorgestrel) The PK parameters of the OC components measured
with and without lacosamide coadministration were
Ratio cycle 3/cycle
Pharmacokinetic Cycle 2 Cycle 3 2 Point estimatea
almost all within the bioequivalence range, indicating that
parameter (n = 36) (n = 31) (90% CI) lacosamide did not significantly affect the PK profile of
Ethinylestradiol
the OC. There was a tendency for increased AUC0-24,ss
AUC0-24 h,ss 1,067  404 1,173  330 1.113 (1.052–1.117) and Cmax,ss for both ethinylestradiol and levonorgestrel
(pg h/ml) during lacosamide coadministration; however, with the
Cmax,ss (pg/ml) 116.9  48.8 135.7  28.6 1.205 (1.106–1.312) exception of the point estimate and 90% CIs for ethiny-
tmax,ss (h) 1.5  0.6 1.4  0.7 NP lestradiol for Cmax,ss (1.205, 1.106–1.312), the remaining
Levonorgestrel
AUC0-24 h,ss 74.2  21.4 80.9  18.5 1.092 (1.046–1.140)
point estimates and 90% CIs for the AUC0-24,ss and
(ng h/ml) Cmax,ss ratios for ethinylestradiol and levonorgestrel were
Cmax,ss (ng/ml) 6.7  1.9 7.4  1.5 1.120 (1.053–1.192) entirely contained within the acceptance range of 80–125%.
tmax,ss (h) 1.5  1.0 1.1  0.6 NP The increase in ethinylestradiol Cmax,ss is not considered
Lacosamide clinically relevant.
AUC0-12 h,ss – 113.5  20.7 –
(lg h/ml)
The PK characteristics of lacosamide when taken con-
Cmax,ss (lg/ml) – 13.8  2.2 – currently with the OC (AUC of 113.5  20.7 lg h/ml,
tmax,ss (h) – 1.1  0.4 – Cmax of 13.8  2.2 lg/ml, tmax of 1.1  0.4 h, t½ of
t1/2 (h) – 15.3  2.0 – 15.3  2.0) were consistent with those reported earlier
Clf (L/h) – 1.8  0.3 – for lacosamide alone (with adaptation for the ~30% dif-
Vz/f – 39.4  5.1 –
ference in body weight): AUC of 79.7  13.4 and
NP, comparison not performed. Data presented for Cycle 2 and 3 are mean 82.7  13.9 lg h/ml, Cmax of 9.1  1.6 lg/ml, tmax of
 SD
a
Degrees of Freedom = 30. 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
During cycle 3, in the time interval when the OC and of lacosamide. These results suggest that concomitant
lacosamide were coadministered, an increase in the fre- administration of lacosamide and OCs will not affect the
quency of skin- and central nervous system (CNS)–related anticonvulsant properties of lacosamide.
AEs was observed compared with cycle 2 when the OC was No serious AEs occurred during this trial. A greater
administered alone. Skin-related AEs included erythema, number of AEs—including skin-related reactions, tired-
exanthema, itching, pruritus, pustular rash, rosacea, and dry ness, dizziness, and paresthesia of the mouth—were
skin. The most frequent CNS-related AEs judged as proba- reported during coadministration of lacosamide and the
bly related to lacosamide were paresthesia of the mouth OC compared with treatment with the OC alone; however,
(13), tiredness (8), and dizziness (7). Three women reported these were mild or moderate in intensity and none led to
ongoing AEs at follow-up: one with paraesthesia, tinnitus, study withdrawal. No clinically relevant changes in clinical
impaired writing and hematoma; one with eosinophilia; and laboratory values, cardiovascular, or ECG parameters were
one with headache dizziness and ear pain. With the excep- observed during coadministration of lacosamide and the
tion of the one volunteer with eosinophilia (reported as an OCs.
AE in cycle 2, OC alone) there were no clinically relevant The limitation of this trial is that only the PK and PD
changes in laboratory values, ECG studies, vital signs, or interactions of lacosamide with the ethinylestradiol plus
physical examination. 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
Discussion additional concomitant AEDs is not known.
In this open-label trial in healthy females, lacosamide In conclusion, coadministration of the ethinylestradiol plus
400 mg/day did not affect ovulation suppression by an OC levonorgestrel combination OC with lacosamide was gener-
(ethinylestradiol plus levonorgestrel) as confirmed by ally well tolerated and did not appear to result in clinically
serum progesterone levels. In each of the 31 women who meaningful PD or PK interactions. These results suggest that
completed the trial, serum progesterone concentration did the ethinylestradiol plus levonorgestrel combination OCs can
not exceed 5.1 nM on day 21 of cycle 3 (lacosamide plus be used in patients receiving lacosamide without the risk of
OC), the criterion for successful ovulation suppression. contraceptive failure or loss of seizure control.
Epilepsia, 54(3):530–536, 2013
doi: 10.1111/epi.12085
536
W. Cawello et al.

Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. (1990) The
Acknowledgments interaction of phenytoin and carbamazepine with combined oral
contraceptive steroids. Br J Clin Pharmacol 30:892–896.
This study was funded by UCB Pharma. The cooperation and contribu-
Doose DR, Wang SS, Padmanabhan M, Schwabe S, Jacobs D, Bialer M.
tion made by the volunteers and their families is gratefully recognized. The
(2003) Effect of topiramate or carbamazepine on the
clinical study, as well the statistical analysis, was performed by PAREXEL
pharmacokinetics of an oral contraceptive containing norethindrone
International GmbH, Berlin, Germany. Laboratory services were provided
and ethinyl estradiol in healthy obese and nonobese female subjects.
by Dr. H. Tabel and Dr. T. Wurche, Gesellschaft mbH f€ur Labortechnologie
Epilepsia 44:540–549.
in Wissenschaft und Technik, Berlin, Germany, and measurements of drug
Doty P, Rudd GD, Stoehr T, Thomas D. (2007) Lacosamide.
concentrations in plasma were performed by NUVISAN GmbH, Neu-Ulm,
Neurotherapeutics 4:145–148.
Germany. Merrilee Johnstone, PhD, from Prescott Medical Communica-
Eldon MA, Underwood BA, Randinitis EJ, Sedman AJ. (1998) Gabapentin
tions Group (Chicago, IL) as well as Azita Tofighy, PhD, from UCB
does not interact with a contraceptive regimen of norethindrone acetate
Pharma (Brussels, Belgium) provided writing assistance.
and ethinyl estradiol. Neurology 50:1146–1148.
Fountain N, Staelens L, Tytgat D, Rudd GD, Jacques P, Cawello W. (2012)
Low lacosamide plasma protein binding in lacosamide-naive patients
Disclosure (abstract). Neurology 78:P01.077.
Gatti G, Bonomi I, Jannuzzi G, Perucca E. (2000) The new antiepileptic
Willi Cawello is an employee of UCB Pharma, Monheim, Germany. drugs: pharmacological and clinical aspects. Curr Pharm Des 6:
The remaining authors declare no conflicts of interest. We confirm that we 839–860.
have read the Journal’s position on issues involved in ethical publication Guengerich FP. (1988) Oxidation of 17 alpha-ethynylestradiol by human
and affirm that this report is consistent with those guidelines. liver cytochrome P-450. Mol Pharmacol 33:500–508.
Guengerich FP. (1990) Mechanism-based inactivation of human liver
microsomal cytochrome P-450 IIIA4 by gestodene. Chem Res Toxicol
References 3:363–371.
Horstmann R, Bonn R, Cawello W, Doty P, Rudd GD. (2002) Basic clinical
Back DJ, Orme ML. (1990) Pharmacokinetic drug interactions with oral pharmacologic investigations of the new antiepileptic drug SPM 927
contraceptives. Clin Pharmacokinet 18:472–484. (abstract). Epilepsia 43:188.
Bartoli A, Gatti G, Cipolla G, Barzaghi N, Veliz G, Fattore C, Mumford J, Hovinga CA. (2003) SPM-927 (Schwarz Pharma). IDrugs 6:479–485.
Perucca E. (1997) A double-blind, placebo-controlled study on the Johannessen Landmark C, Patsalos PN. (2010) Drug interactions involving
effect of vigabatrin on in vivo parameters of hepatic microsomal the new second- and third-generation antiepileptic drugs. Expert Rev
enzyme induction and on the kinetics of steroid oral contraceptives in Neurother 10:119–140.
healthy female volunteers. Epilepsia 38:702–707. Penovich PE. (2004) Do new antiepileptic drugs interact with oral
Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, contraceptives? Epilepsy Curr 4:31–32.
Tomson T. (2007) Progress report on new antiepileptic drugs: a Ragueneau-Majlessi I, Levy RH, Janik F. (2002) Levetiracetam does not
summary of the Eighth Eilat Conference (EILAT VIII). Epilepsy Res alter the pharmacokinetics of an oral contraceptive in healthy women.
73:1–52. Epilepsia 43:697–702.
Cawello W, Bonn R. (2012) No pharmacokinetic interaction between Reddy DS. (2010) Clinical pharmacokinetic interactions between
lacosamide and valproic acid in healthy volunteers. J Clin Pharmacol antiepileptic drugs and hormonal contraceptives. Expert Rev Clin
52:1739–1748. Pharmacol 3:183–192.
Cawello W, Nickel B, Eggert-Formella A. (2010) No pharmacokinetic Sabers A. (2008) Pharmacokinetic interactions between contraceptives and
interaction between lacosamide and carbamazepine in healthy antiepileptic drugs. Seizure 17:141–144.
volunteers. J Clin Pharmacol 50:459–471. Shorvon SD, Tallis RC, Wallace HK. (2002) Antiepileptic drugs:
Cawello W, Boekens H, Bonn R. (2012) Absorption, disposition, metabolic coprescription of proconvulsant drugs and oral contraceptives: a
fate and elimination of the anti-epileptic drug lacosamide in humans: national study of antiepileptic drug prescribing practice. J Neurol
mass balance following intravenous and oral administration. Eur J Neurosurg Psychiatry 72:114–115.
Drug Metab Pharmacokinet 37(4):241–248. Thomas D, Scharfenecker U, Schiltmeyer B, Cawello W, Doty P,
Cawello W, B€ okens H, Nickel B, Andreas JO, Halabi A. (2013) Horstmann R. (2007) Low potential for drug-drug-interaction of
Tolerability, pharmacokinetics and bioequivalence of the tablet and lacosamide (abstract). J Pain 8:S39.
syrup formulations of lacosamide in plasma, saliva and urine: saliva as UCB. (2011) Vimpatâ (lacosamide) tablets, injection and oral solution [U.
a surrogate of pharmacokinetics in the central compartment. Epilepsia S. prescribing information]. UCB, Inc., Smyrna, GA.
54(1):81–88. Wilbur K, Ensom MH. (2000) Pharmacokinetic drug interactions between
Clopper CJ, Pearson ES. (1934) The use of confidence or fiducial oral contraceptives and second-generation anticonvulsants. Clin
limits illustrated in the case of the binomial. Biometrika 26:404–413. Pharmacokinet 38:355–365.

Epilepsia, 54(3):530–536, 2013

doi: 10.1111/epi.12085