Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Pharmaceutical Science to Improve the Human Condition: Prix Galien 2013
Advances in epilepsy treatment: lacosamide pharmacokinetic profile Willi Cawello,1 Armel Stockis,2 Jens-Otto Andreas,1 and Svetlana Dimova2 1
UCB Pharma, Monheim, Germany. 2 UCB Pharma, Brussels, Belgium
Address for correspondence: Willi Cawello, Ph.D., Principal Quantitative Scientist, Global Statistical Sciences, UCB Pharma, Alfred-Nobel-Str. 10, 40789 Monheim, Germany. [email protected]
Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial-onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose-proportional pharmacokinetics, low inter- and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug–drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug–drug interactions, make LCM an easy-to-use adjunctive treatment for the management of patients with focal epilepsy. Keywords: lacosamide; pharmacokinetics; drug–drug interactions; focal epilepsy
Introduction Epilepsy is one of the most common chronic central nervous system disorders, affecting over 65 million people worldwide, 60% of whom are diagnosed with partial-onset seizures.1–3 Treatment of epilepsy with antiepileptic drugs (AEDs) is aimed at preventing new seizures or reducing the severity of seizures, without decreasing quality of life due to complications from adverse reactions or interactions with other treatments.2,4 Because epilepsy is a chronic condition, patients frequently require longterm, potentially lifelong treatment with AEDs. A staged approach to the pharmacologic management of patients with AEDs is recommended;5 however, more than 30% of patients remain uncontrolled and will require AED polytherapy.6,7 Effective polytherapy requires understanding the metabolic pathways of each AED to avoid the risk of pharmacokinetic drug–drug interactions. Many patients with epilepsy also require pharmacologic treatment for
other medical conditions, necessitating an understanding of the potential for pharmacokinetic drug– drug interactions across multiple drug classes. Selection of an AED is dependent on several patient- and drug-specific factors, some of which are related to the pharmacokinetic properties of the drug, such as dosing frequency, pharmacokinetics, interaction potential, and available formulations.8–10 Desirable pharmacokinetic characteristics of an AED include rapid and complete oral absorption, linear pharmacokinetics, longer half-life, absence of active metabolites, absence of autoinduction properties, minimal induction or inhibition of principal drug-metabolizing hepatic enzymes, rapid penetration through the blood–brain barrier and entry into the brain, low inter- and intrasubject variability, renal elimination, and low plasma protein binding.4,11–13 Every AED has a characteristic pharmacokinetic profile that has been derived from singleand multiple-dose studies in healthy subjects, doi: 10.1111/nyas.12513
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special populations, and in the target population. Limitations of some of the older AEDs include a nonlinear pharmacokinetic profile, high inter- and intraindividual variability, narrow therapeutic window between efficacy and toxicity, or induction (including autoinduction) or inhibition of the drug-metabolizing enzymes.14 Therefore, while new AEDs are expected to demonstrate comparable efficacy to existing drugs, they also need to have pharmacokinetic properties (i.e., the absorption, distribution, metabolism, and elimination) that make them easy to use with concomitant treatments (AEDs and non-AED drugs) to minimize risk (safety) to patients. Indeed, in terms of overall drug development, concerns surrounding efficacy, safety, and inadequate dosing lead to the failure in obtaining Food and Drug Administration (FDA) approval in 13.2%, 53.8%, and 15.9%, respectively, of firsttime new drug applications from the year 2000 to 2012, all of which are related in various ways to the pharmacokinetic characteristics of the drug.14,15 Thus, characterizing the pharmacokinetic profile of a drug candidate is an important factor in the early phases of AED development. Lacosamide (LCM; R-2-acetamido-N-benzyl-3R , UCB Pharma, methoxypropionamide; Vimpat Brussels, Belgium) is a functionalized amino acid that has been specifically developed as an AED.16 Functionalized amino acids are amino acid derivatives in which substitutions of specific chemical groups generate a molecule where the R-isomer has greater potency than the S-isomer.17,18 LCM is an analogue of d-serine that has amphiphilic properties that allow the molecule to be water soluble enough to be formulated into a parenteral product and lipophilic enough to cross the blood–brain barrier.17 Preclinical studies have demonstrated that LCM does not affect the sodium channel fast inactivation, a typical mechanism of action of the traditional sodium channel-blocking AEDs.16,19,20 Instead, LCM acts by selective enhancement of the slow inactivation phase of voltage-gated sodium channels.19,21 Other potential molecular mechanisms have been reported for LCM, including inhibition of carbonic anhydrase22 and interaction with the collapsin response mediator protein 2,23 although the later mechanism remains controversial.24 LCM is approved for the adjunctive treatment of partial-onset seizures in patients with epilepsy (aged 17 years in the United States,25 16 years in
Lacosamide pharmacokinetics
Europe26 ). The recommended initial dose of LCM is 50 mg twice daily (BID; 100 mg/day). The dose may be increased by 100 mg/day in weekly intervals given as two divided doses up to a recommended therapeutic daily dose of 200–400 mg/day, depending on individual patient response and tolerability.25,26 The efficacy and safety of LCM as adjunctive therapy for adults with focal epilepsy in doses ranging from 200 (100 mg BID) to 600 mg/day (300 mg BID) has been established in multicenter, randomized, placebocontrolled clinical trials.27–29 Common treatmentemergent adverse events reported in phase 2/3 LCM adjunctive therapy clinical trials (incidence 10% and greater than placebo) were dizziness, headache, nausea, and diplopia.25–29 An overview of the efficacy and safety of LCM from these and other clinical studies has been published in an earlier volume of this journal,21 but information on pharmacokinetic profile of LCM was limited. This review provides an overview of the clinical pharmacology of LCM, including data on clinical pharmacokinetics and drug–drug interaction studies in healthy subjects and adults with focal epilepsy. The data reviewed in this article will provide the clinician with a fundamental understanding of the development of LCM from a pharmacokinetic perspective, its pharmacokinetic profile in different populations, and the performed drug–drug interaction studies. General pharmacokinetic overview Multiple clinical pharmacology studies in healthy subjects (aged 18–87 years) and in patients with focal epilepsy (aged 16 years), established the overall absorption, distribution, metabolism, and elimination properties of LCM. Data from these studies have indicated that LCM demonstrates favorable characteristics among AEDs, including a high oral bioavailability,30,31 linear pharmacokinetic profile,32,33 dose proportionality with low interand intraindividual variability,31,32 and low potential for clinically relevant pharmacokinetic drug– drug interactions.34–38 These results are important because they establish the predictable pharmacokinetic profile of LCM and help the clinician shape decisions to achieve the desired drug-response profile.39 Absorption LCM is rapidly and completely absorbed (100% absolute bioavailability) from the gastrointestinal
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Cawello et al.
30
400
Cmax
AUC
350
25
20 250
Cmax (µg/mL)
AUC (µg/mL·h)
300
200 150
15
10
100
Single-dose AUC0–inf Multiple-dose AUCtau,ss
50
Single-dose: Cmax Multiple-dose: Cmax,ss
5
0
0 0
100 200 300 400 500 600 700 800 900 Lacosamide dose (mg)
0
100 200 300 400 500 600 700 800 900 Lacosamide dose (mg)
Linear regression based on the arithmetic means from the individual studies
Figure 1. LCM AUC and Cmax in healthy subjects following single or multiple oral dosing (linear regression based on the arithmetic means ± SD). The approved daily dose for adjunctive LCM is up to 400 mg/day (200 mg BID). AUC, area under the concentration time curve; Cmax , peak plasma concentration; LCM, lacosamide; SD, standard deviation.
tract with peak plasma concentrations (Cmax ) occurring about 0.5–4 h postdose in healthy subjects.26 Study in healthy subjects has shown that the rate and extent of LCM gastrointestinal absorption are not altered by food intake,40 thereby simplifying the dosing regimen of a patient allowing administration irrespective of meals. Following oral administration, LCM shows linear pharmacokinetics (Fig. 1) that are constant over time, with low intra- and intersubject variability.25,26,30 LCM pharmacokinetic parameters were generally consistent between healthy subjects (Table 1) and adults with focal epilepsy (Table 2). Distribution The volume of distribution (Vd) of LCM is 0.6 L/kg, which is close to the volume of the total body water.25,26 The low plasma protein binding ( CLCR 50 mL/min) Moderate (50 mL/min > CLCR 30 mL/min) Severe (CLCR 20–30 mL/min or < 20 mL/min) ESRD (no hemodialysis; CLCR < 15 mL/min) ESRD (hemodialysis; CLCR < 15 mL/min) Korean subjects Kim et al.57
Drug interaction studies Carbamazepine Cawello et al.37
Valproic acid
Cawello et al.34
Application Tablet 15 min IV Tablet 30 min IV 60 min IV Tablet Oral solution Oral solution 60 min IV
Tablet
No. subjects
Dose (mg)
16 16 23 24 25 16 16 5 5
200 (2 × 100 mg) 200 (200 mg/20 mL) 200 (2 × 100 mg) 200 (200 mg/20 mL) 200 (200 mg/20 mL) 200 (2 × 100 mg) 200 (200 mg/mL) 100 (100 mg/5 mL) 100 (100 mg/40 mL)
8
100
Single Single Single Single Single Single Single Single Single
4.76 (23.6) 5.72 (36.3) 4.93 (27.9) 5.76 (28.0) 5.26 (22.5) 5.26 (19.8) 5.14 (16.5) 3.36 (0.603)c 3.38 (0.327)c
0.75 (0.28–4.0)b 0.25 (0.25–2.0)b 0.75 (0.25–4.0)b 0.5 (0.5–2.0)b 1.0 (1.0–3.0)b 1.0 (0.5–1.5)b 0.5 (0.5–2.0)b 0.60 (0.22)c 1.30 (0.45)c
76.50 (18.4) 75.40 (17.0) 79.54 (24.9) 79.84 (24.6) 80.53 (25.6) 84.51 (22.2) 83.31 (21.8) 62.20 (10.0)c 71.8 (7.0)c
13 (10.1–16.2)b 12.6 (10.8–16.1)b 11.2 (9.3–18.0)b 11.4 (9.3–17.0)b 11.3 (9.5–17.2)b 12.5 (19.1) 12.4 (18.3) 15.0 (3.27)c 16.3 (2.03)c
Single
2.69 (35.0)
1.00 (0.5–2.0)b
47.01 (20.8)
13.2 (17.6)
59.62 (17.5)
18.2 (18.7)
t1/2 (h)
Tablet
8
100
Single
2.95 (20.7)
Tablet
8
100
Single
3.06 (10.0)
0.50 (0.5–1.0)b
57.57 (19.0)
15.4 (18.9)
Tablet
8
100
Single
3.02 (23.3)
1.00 (0.5–1.5)b
74.76 (26.9)
18.3 (27.8)
Tablet
8
100
Single
3.18 (22.4)
0.50 (0.5–4.0)b
73.37 (26.3)
19.6 (19.4)
Tablet
8
100
Single
2.79 (22.1)
0.70 (0.5–2.0)b NA
19.2 (26.8)
Tablet Tablet Tablet Tablet Tablet
12 12 12 12 12
50 100 200 100 BID 200 BID
0.5 (0.5–1.5)b 27.55 (15.1) 0.75 (0.5–2.0)b 52.71 (14.4) 1.5 (0.5–4.0)b 116.69 (16.5) 52.10 (17.0) 0.5 (0.5–2.0)b 0.5 (0.50–1.0)b 112.35 (13.0)
15.3 (12.0) 15.0 (16.5) 15.9 (12.4) 16.0 (14.6) 16.7 (11.7)
Tablet
19
200 mg BID
2.2 (0.9)c
83.3 (14.0)c
12.8 (1.4) (n = 9)
Tablet
18
200 mg BID
2.4 (1.0)c
79.7 (13.4)c
Capsule
16
200 mg BID
0.8 (0.5–3.0)b
82.9 (13.8)c
Capsule
15
200 mg BID
0.5 (0.5–1.0)b
82.7 (13.9)c
0.93 (0.61)c
83.2 (11.4)c
12.8 (2.0) (n = 10) 13.2 (10.7–18.7) (n = 8)b 15.6 (10.7–19.1) (n = 7)b —
Cawello et al.35
Tablet
20
200 mg BID
Omeprazole
Cawello et al.36
Tablet
34
300
Tablet
34
300
Tablet
31
200 mg BID
Cawello et al.54
tmax a (h)
0.50 (0.5–1.0)b
Digoxin
R Microgynon
AUCa (g/mL h)
Cmax a (g/mL)
Dosing schedule
Single Single Single Multiple Multiple
1.63 (9.1) 2.85 (14.6) 5.84 (24.3) 6.23 (15.0) 13.13 (8.9)
Multiple 9.9 (2.0)c (LCM + CBZ) Multiple 9.1 (1.6)c LCM alone Multiple 9.7 (1.2)c LCM + VPA Multiple 9.5 (1.3)c LCM alone Multiple 9.5 (1.1)c LCM + digoxin Single 7.335 (16.9) LCM + OMZ Single 7.366 (19.8) LCM alone Multiple 13.8 (2.2)c LCM + microgynon
1.00 (0.5–3.0)b 160.3 (22.4)
16.2 (13.5)
1.00 (0.5–3.0)b 134.0 (22.1)
13.2 (12.7)
1.1 (0.4)c
15.3 (2.0)c
113.5 (20.7)c
a
tmax , Cmax , and AUC represent values after single dose or steady state after multiple twice-daily dosing. Median (range). c Arithmetic mean ± standard deviation. AUC, area under the curve; BID, twice daily; Cmax , maximum plasma concentration; CBZ, carbamazepine; CLCR , creatinine clearance; ESRD, end-stage renal disease; IV, intravenous infusion; LCM, lacosamide; NA, not available; OMZ, omeprazole; tmax , time to maximum plasma concentration; t1/2 , half-life; VPA, valproic acid. b
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Table 2. Summary of adjunctive LCM pharmacokinetics at end of maintenance in adults with focal epilepsy
Mean plasma concentration (g/mL) (SD)
Ctrough (g/mL) (SD)
4.99 (2.51) 9.35 (4.22) 12.46 (5.80)
NA NA NA
Application
No. of subjectsa
Dose (mg/day)
Dosing schedule
Ben-Menachen et al.
Tablet Tablet Tablet
85 83 61
200 400 600
Multiple
Haslaz et al.29
Tablet Tablet
163a 159a
200 400
Multiple
3.8b 7.4b
NA NA
Chung et al.28
Tablet Tablet
204a 97a
400 600
Multiple
7.19b 9.5b
NA NA
Krauss et al.56
IV infusion IV infusion IV infusion
14 25 17
200 400 600
Multiple
Fountain et al.55
Loading IV Loading IV Loading IV
25 50 25
200c 300c 400c
Single
Study 27
5.5 (1.2) 10.5 (2.5) 15.9 (4.1) 6.59 (2.22) 9.32 (3.77) 12.33 (4.12)
2.6 (0.8) 4.7 (1.4) 7.7 (2.7) NA NA NA
a
Patients randomized to LCM. Standard deviation not provided. c Single dose in mg. All values are mean (SD), unless otherwise indicated. IV, intravenous infusion; NA, not available; LCM, lacosamide; SD, standard deviation. b
levels of metabolites. Finally, drug-metabolizing enzymes can be affected by genetic mutations resulting in increased, decreased, or suppressed activity, and the incidence of such mutations can differ substantially (from rare to frequent) among different ethnic groups. Thus, knowledge of the enzymatic pathways involved in drug metabolism, and whether the drug may induce or inhibit such enzymes, can help the clinician provide optimal therapy and avoid potential drug interactions.49 Following oral or intravenous (IV) administration of 100 mg (40 Ci) [14 C]-LCM in healthy subjects, the majority of the radioactivity in plasma was found to be unchanged LCM (61–71% after oral administration; 71–81% after IV infusion).30 LCM is metabolized primarily via demethylation to the O-desmethyl metabolite (elimination halflife 15–23 h), which has no known pharmacological activity.30,50,51 The plasma exposure of O-desmethyl-lacosamide is approximately 10–15% that of LCM.25,26 The metabolic profile of LCM remains similar following oral administration or IV infusion, suggesting no first-pass effect following oral administration.30
22
Studies have suggested CYP2C19 as the main CYP isoform implicated in the demethylation of LCM. In addition to CYP2C19, in vitro data indicated that CYP3A4 and CYP2C9 catalyze the formation of the LCM O-desmethyl metabolite.25,26 The metabolism of LCM by three CYP isozymes reduces the likelihood of drug interactions because the metabolism of the drug is not dependent on one specific CYP pathway. In healthy male or female subjects, no clinically relevant changes in plasma concentrations (based on Cmax and AUC) have been observed when LCM was coadministered with CYP substrates and inducers, such as midazolam (CYP3A4), or inhibitors, such as omeprazole (CYP2C19).36,52 LCM plasma concentrations were similar between CYP2C19 poor and extensive metabolizers; however, plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were reduced by 70% in CYP2C19 poor metabolizers compared to the extensive metabolizers.25 In addition, coadministration of a CYP2C19 substrate and inhibitor, omeprazole, reduced the formation of O-desmethyl-lacosamide by approximately 60%.36
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These two studies indicate the involvement of CYP2C19 in the demethylation of LCM. Elimination LCM is eliminated primarily by the kidneys, with less than 1% of the dose eliminated by the feces.26,30 Following oral or IV administration of [14 C]-LCM in healthy subjects, the total radioactivity was excreted relatively quickly, with a mean of 82% of the administered dose excreted within 48 h and approximately 95% excreted within 168 h postdose, indicating no accumulation of unchanged LCM or its metabolites in red blood cells or other tissues.26,30 Apparent plasma clearance (CL/F) in healthy subjects and patients with focal epilepsy (and in all aspects of consideration, e.g., ethnicity, symptoms like decreased renal function as well as coadministration of other drugs) was between 1.34 and 2.65 L/h.36,53,54 The cumulative urinary excretion consisted mainly of unchanged LCM (40% of a dose), the primary metabolite, O-desmethyl-lacosamide (30%), and a polar fraction of compound(s) not further identified (20%).30,51 Additional metabolites were identified only in small amounts ( 30 mL/min), and 100 mg (followed by 50 mg BID regimen in the first 7 days) in patients with severe renal impairment (CLCR 30 mL/min) may be considered, but further dose titration should likewise be performed with caution. 26 At the time of this writing, a loading dose of LCM is not indicated for use in the United States. In addition, LCM exposure may be increased in patients with
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renal impairment who are taking strong CYP3A4 and CYP2C9 inhibitors; LCM dose reduction may be necessary in these patients.25 Hemodialysis significantly affects systemic LCM exposure. In patients with ESRD, the mean extraction rate of LCM during hemodialysis was 57%.53 More specifically, after a single 100 mg oral dose of LCM, exposure (based on AUC) was 50% lower in patients receiving hemodialysis versus dosing on a hemodialysis-free day. Therefore, LCM dosage supplementation up to 50% of the divided daily dose directly after the end of hemodialysis should be considered.25,26 Although it has not been used in the few known cases, standard hemodialysis may result in a 50% reduction of systemic LCM exposure in 4 h and may be indicated in the event of LCM overdose.25 Patients with hepatic impairment Subjects with moderate hepatic impairment (ChildPugh B) on steady-state LCM (200 mg/day for 4.5 days) showed increases in LCM exposure (based on AUCss ) of 50–60% compared with healthy controls.25,26 Based on this, a maximum dose of 300 mg/day is recommended in the United States for patients with mild or moderate hepatic impairment.25 The higher exposure in subjects with moderate hepatic impairment was caused in large part to reduced renal function in these subjects compared with healthy controls as the decrease in nonrenal clearance in the subjects was estimated to give a 20% increase in the AUC of LCM.26 Based on this, in Europe no dose adjustment is recommended in patients with mild or moderate hepatic impairment.26 Recommendations in Europe for use of LCM as a single loading dose in patients with hepatic impairment are similar to those discussed above for patients with mild/moderate renal impairment; a single loading dose of 200 mg may be considered, with any further dose titration then performed with caution.26 It should also be noted that pharmacokinetics of LCM have not been systematically evaluated in patients with severe hepatic disease, and as a result the use of LCM in patients with severe hepatic impairment is not recommended. Significant increases in LCM exposure may occur in patients with hepatic impairment who are taking strong CYP3A4 and CYP2C9 inhibitors. LCM dose reduction may be necessary in these patients.25
Lacosamide pharmacokinetics
Drug–drug interactions Many factors contribute to an increased likelihood of drug–drug interactions, including extensive metabolism, the capacity to induce or inhibit enzymes involved in drug metabolism, formation of active metabolites, and high plasma protein binding. For AEDs, the risk of drug–drug interactions is highlighted mainly by older AEDs, most of which are known inducers or inhibitors of drug metabolizing enzymes.65,66 In vitro studies suggested that, at clinically relevant concentrations observed in clinical studies, LCM did not induce the activity of CYP isoforms 1A2, 2B6, 2C9, 2C19, or 3A4 or inhibit the activity of CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, or 3A4/5.25,26 In vitro data suggest, however, that LCM is a substrate for and moderate inhibitor of CYP2C19.30,50 These results suggest that LCM should not affect the metabolism of drugs undergoing CYP-mediated biotransformation. A number of in vivo drug–drug interaction studies have been conducted to assess the potential of LCM to interact with commonly used AEDs and other therapeutic agents, both in healthy subjects and in patients with focal epilepsy. These studies have demonstrated that LCM has a low potential for clinically relevant pharmacokinetic drug–drug interactions. AEDs Drug–drug interaction–specific studies conducted in healthy male subjects found that administration of LCM (200 mg BID) does not affect the pharmacokinetics of carbamazepine (CBZ; 200 mg BID) or valproic acid (VPA; 300 mg BID) and that CBZ and VPA do not affect the pharmacokinetics of LCM, based on AUC and Cmax at steady state (Table 1).34,37 Data pooled from phase III placebo-controlled studies in adults with focal epilepsy have shown that LCM does not affect the plasma concentration of concomitantly administered AEDs, including levetiracetam, carbamazepine and carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide.26 A separate population pharmacokinetic analysis showed small (15–20%) reductions in LCM plasma concentrations when LCM was coadministered with enzyme-inducing AEDs, such as carbamazepine, phenobarbital, or phenytoin.25
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However, no dose adjustment is required in patients on concomitant enzyme-inducing AEDs. The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system. LCM has been shown to cause dose-related prolongation of the PR interval,25,26 and conduction abnormalities have been associated with carbamazepine treatment.67 A multiple-dose, open-label study evaluating the interaction between LCM and carbamazepine in healthy male patients did not demonstrate an increased magnitude of PR prolongation.37 Further, an increased magnitude of PR prolongation in patients treated with LCM and concomitant carbamazepine or lamotrigine was not identified in a clinical study subgroup analysis.26 LCM should be used with caution in patients with known conduction problems (e.g., marked first-degree atrioventricular block, second-degree or higher atrioventricular block and sick sinus syndrome without pacemaker, sodium channelopathies (Brugada Syndrome), on concomitant medications that prolong PR interval, or with severe cardiac disease such as myocardial ischemia or heart failure, or structural heart disease). In such patients, obtaining an ECG before beginning LCM, and after LCM is titrated to steady state, is recommended.25 Other (non-AED) drug–drug interaction studies in healthy subjects Warfarin. Warfarin has a narrow therapeutic index (optimal international normalized ratio (INR) 2–3),68 and plasma levels outside the therapeutic range may lead to increased risk of thrombotic events or bleeding.69 Warfarin is a mixture of enantiomers in which the R-enantiomer is primarily metabolized by CYP1A2 and 3A4 and the S-enantiomer by CYP2C9.70 Drugs that compete as substrates or inhibit the activity of these CYP isoforms may increase warfarin plasma concentrations, potentially increasing the risk of bleeding.70 Coadministration of LCM (400 mg/day (200 mg BID)) did not alter the pharmacokinetics of warfarin (25 mg), as the mean plasma concentration–time profiles for the warfarin S- and R-enantiomers remained unchanged following LCM coadministration.38 The level of anticoagulation in subjects receiving warfarin was also shown to be unaffected by concomitant intake of 28
LCM. These results suggest that there is no need for dose adjustment of warfarin when coadministered with LCM.38 Digoxin. Digoxin metabolism is independent of the CYP450 system, and digoxin is not known to induce or inhibit CYP isozymes.71 Digoxin is, however, a P-glycoprotein substrate and dependent on the glycoprotein for intestinal absorption and renal elimination.72 Because of digoxin’s dependency on P-glycoprotein, digoxin has become the standard for evaluating P-glycoprotein–mediated potential drug–drug interactions.72 Digoxin has a narrow therapeutic window, and small changes in exposure may decrease efficacy or increase toxicity.73 Coadministration of digoxin (0.25 mg/day) with LCM (400 mg/day; multiple doses) versus digoxin alone revealed no differences in digoxin exposure.35 These results suggest that LCM would not be expected to affect the disposition of P-glycoprotein substrates.35 A small increase was noted in the PR interval for coadministered digoxin plus LCM compared with either drug administered alone. LCM should be used with caution in patients treated with products known to be associated with PR prolongation and in patients treated with class 1 antiarrhythmics.25,26 Omeprazole. Omeprazole is a proton-pump inhibitor that is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4. Therefore, drugs that affect the activity of these CYP isozymes, particularly CYP2C19, may influence the metabolism of omeprazole.74 Omeprazole also acts as a CYP2C19 inhibitor, and may affect the metabolism of drugs metabolized by this enzyme.74 In healthy male subjects with normal CYP2C19 activity, multiple-dose LCM (200 mg BID) administration (at steady state) did not affect the pharmacokinetics of single-dose omeprazole (40 mg). Multiple-dose omeprazole administration (40 mg/day) did not influence LCM single-dose (300 mg) pharmacokinetics (Table 1).36 These data suggest that LCM exposure is unlikely to be affected to a clinically relevant extent by moderate CYP2C19 inhibitors. However, caution is recommended when LCM is coadministered with strong CYP2C9 inhibitors (e.g., fluconazole).26 Although omeprazole did not significantly affect the pharmacokinetics of LCM, formation of O-desmethyllacosamide was reduced (60%) with omeprazole coadministration, supporting that CYP2C19 is the
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main CYP isoform involved in the demethylation of LCM.36 Midazolam. Midazolam is mainly metabolized by CYP3A4.75 Midazolam has been used as a test substrate to assess the effect of drugs on the activity of 3A4.76 In healthy subjects, single (200 mg) and multiple doses (400 mg/day) of LCM did not affect the metabolism of a single dose (7.5 mg) of midazolam. In addition, the AUC confidence intervals for all treatments fell within the accepted 80–125% bioequivalence range.52 However, the midazolam Cmax was slightly elevated (30%) when coadministered with 400 mg (200 mg BID) LCM.26 The in vivo data therefore support that no clinically relevant induction or inhibition of CYP34A by LCM occurs at clinically relevant doses in healthy subjects. Combined oral contraceptive (OC). The combined OC contains a progestin (e.g., levonorgestrel or norethindrone) and an estrogen (usually ethinylestradiol), both of which are metabolized by CYP enzymes.77 Several AEDs, including older (carbamazepine, phenytoin, phenobarbital, and primidone) and newer AEDs (oxcarbazepine, topiramate (>200 mg), and eslicarbazepine acetate) are CYP3A4 enzyme inducers and may reduce the plasma concentrations of OC, and therefore have the potential to compromise contraception.66 Moreover, many women with epilepsy are unaware of these potential interactions that may lead to contraceptive failure.78 It is therefore important to define the potential for interaction between contraceptives and AEDs in order to optimize effective treatment plans for women of child-bearing age with epilepsy. In an open-label study in healthy female subjects, no pharmacokinetic interaction was observed between LCM (400 mg/day) and the combined OC containing ethinylestradiol (0.03 mg) plus levonorgestrel (0.15 mg).54 The study found the same level of progesterone suppression (
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Pharmaceutical Science to Improve the Human Condition: Prix Galien 2013
Advances in epilepsy treatment: lacosamide pharmacokinetic profile Willi Cawello,1 Armel Stockis,2 Jens-Otto Andreas,1 and Svetlana Dimova2 1
UCB Pharma, Monheim, Germany. 2 UCB Pharma, Brussels, Belgium
Address for correspondence: Willi Cawello, Ph.D., Principal Quantitative Scientist, Global Statistical Sciences, UCB Pharma, Alfred-Nobel-Str. 10, 40789 Monheim, Germany. [email protected]
Lacosamide (LCM) is a functionalized amino acid specifically developed for use as an antiepileptic drug (AED) and is currently indicated as adjunctive treatment for partial-onset seizures in adults with focal epilepsy (maximum approved dose 400 mg/day). Characterization of the pharmacokinetic profile is an important aspect in the development of LCM. Studies in healthy subjects and in patients with focal epilepsy have established that LCM has several favorable pharmacokinetic characteristics, including rapid absorption and high oral bioavailability not affected by food, linear and dose-proportional pharmacokinetics, low inter- and intraindividual variability, low plasma protein binding, renal elimination, and a low potential for clinically relevant pharmacokinetic drug–drug interactions both with AEDs and other common medications. Studies have demonstrated bioequivalence among the three LCM formulations (oral tablets, oral solution, and solution for intravenous (IV) infusion), allowing direct conversion to or from oral and IV administration without titration. Thus, the favorable and predictable pharmacokinetic profile and bioequivalence of LCM formulations, coupled with the low potential for clinically relevant pharmacokinetic drug–drug interactions, make LCM an easy-to-use adjunctive treatment for the management of patients with focal epilepsy. Keywords: lacosamide; pharmacokinetics; drug–drug interactions; focal epilepsy
Introduction Epilepsy is one of the most common chronic central nervous system disorders, affecting over 65 million people worldwide, 60% of whom are diagnosed with partial-onset seizures.1–3 Treatment of epilepsy with antiepileptic drugs (AEDs) is aimed at preventing new seizures or reducing the severity of seizures, without decreasing quality of life due to complications from adverse reactions or interactions with other treatments.2,4 Because epilepsy is a chronic condition, patients frequently require longterm, potentially lifelong treatment with AEDs. A staged approach to the pharmacologic management of patients with AEDs is recommended;5 however, more than 30% of patients remain uncontrolled and will require AED polytherapy.6,7 Effective polytherapy requires understanding the metabolic pathways of each AED to avoid the risk of pharmacokinetic drug–drug interactions. Many patients with epilepsy also require pharmacologic treatment for
other medical conditions, necessitating an understanding of the potential for pharmacokinetic drug– drug interactions across multiple drug classes. Selection of an AED is dependent on several patient- and drug-specific factors, some of which are related to the pharmacokinetic properties of the drug, such as dosing frequency, pharmacokinetics, interaction potential, and available formulations.8–10 Desirable pharmacokinetic characteristics of an AED include rapid and complete oral absorption, linear pharmacokinetics, longer half-life, absence of active metabolites, absence of autoinduction properties, minimal induction or inhibition of principal drug-metabolizing hepatic enzymes, rapid penetration through the blood–brain barrier and entry into the brain, low inter- and intrasubject variability, renal elimination, and low plasma protein binding.4,11–13 Every AED has a characteristic pharmacokinetic profile that has been derived from singleand multiple-dose studies in healthy subjects, doi: 10.1111/nyas.12513
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special populations, and in the target population. Limitations of some of the older AEDs include a nonlinear pharmacokinetic profile, high inter- and intraindividual variability, narrow therapeutic window between efficacy and toxicity, or induction (including autoinduction) or inhibition of the drug-metabolizing enzymes.14 Therefore, while new AEDs are expected to demonstrate comparable efficacy to existing drugs, they also need to have pharmacokinetic properties (i.e., the absorption, distribution, metabolism, and elimination) that make them easy to use with concomitant treatments (AEDs and non-AED drugs) to minimize risk (safety) to patients. Indeed, in terms of overall drug development, concerns surrounding efficacy, safety, and inadequate dosing lead to the failure in obtaining Food and Drug Administration (FDA) approval in 13.2%, 53.8%, and 15.9%, respectively, of firsttime new drug applications from the year 2000 to 2012, all of which are related in various ways to the pharmacokinetic characteristics of the drug.14,15 Thus, characterizing the pharmacokinetic profile of a drug candidate is an important factor in the early phases of AED development. Lacosamide (LCM; R-2-acetamido-N-benzyl-3R , UCB Pharma, methoxypropionamide; Vimpat Brussels, Belgium) is a functionalized amino acid that has been specifically developed as an AED.16 Functionalized amino acids are amino acid derivatives in which substitutions of specific chemical groups generate a molecule where the R-isomer has greater potency than the S-isomer.17,18 LCM is an analogue of d-serine that has amphiphilic properties that allow the molecule to be water soluble enough to be formulated into a parenteral product and lipophilic enough to cross the blood–brain barrier.17 Preclinical studies have demonstrated that LCM does not affect the sodium channel fast inactivation, a typical mechanism of action of the traditional sodium channel-blocking AEDs.16,19,20 Instead, LCM acts by selective enhancement of the slow inactivation phase of voltage-gated sodium channels.19,21 Other potential molecular mechanisms have been reported for LCM, including inhibition of carbonic anhydrase22 and interaction with the collapsin response mediator protein 2,23 although the later mechanism remains controversial.24 LCM is approved for the adjunctive treatment of partial-onset seizures in patients with epilepsy (aged 17 years in the United States,25 16 years in
Lacosamide pharmacokinetics
Europe26 ). The recommended initial dose of LCM is 50 mg twice daily (BID; 100 mg/day). The dose may be increased by 100 mg/day in weekly intervals given as two divided doses up to a recommended therapeutic daily dose of 200–400 mg/day, depending on individual patient response and tolerability.25,26 The efficacy and safety of LCM as adjunctive therapy for adults with focal epilepsy in doses ranging from 200 (100 mg BID) to 600 mg/day (300 mg BID) has been established in multicenter, randomized, placebocontrolled clinical trials.27–29 Common treatmentemergent adverse events reported in phase 2/3 LCM adjunctive therapy clinical trials (incidence 10% and greater than placebo) were dizziness, headache, nausea, and diplopia.25–29 An overview of the efficacy and safety of LCM from these and other clinical studies has been published in an earlier volume of this journal,21 but information on pharmacokinetic profile of LCM was limited. This review provides an overview of the clinical pharmacology of LCM, including data on clinical pharmacokinetics and drug–drug interaction studies in healthy subjects and adults with focal epilepsy. The data reviewed in this article will provide the clinician with a fundamental understanding of the development of LCM from a pharmacokinetic perspective, its pharmacokinetic profile in different populations, and the performed drug–drug interaction studies. General pharmacokinetic overview Multiple clinical pharmacology studies in healthy subjects (aged 18–87 years) and in patients with focal epilepsy (aged 16 years), established the overall absorption, distribution, metabolism, and elimination properties of LCM. Data from these studies have indicated that LCM demonstrates favorable characteristics among AEDs, including a high oral bioavailability,30,31 linear pharmacokinetic profile,32,33 dose proportionality with low interand intraindividual variability,31,32 and low potential for clinically relevant pharmacokinetic drug– drug interactions.34–38 These results are important because they establish the predictable pharmacokinetic profile of LCM and help the clinician shape decisions to achieve the desired drug-response profile.39 Absorption LCM is rapidly and completely absorbed (100% absolute bioavailability) from the gastrointestinal
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19
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Cawello et al.
30
400
Cmax
AUC
350
25
20 250
Cmax (µg/mL)
AUC (µg/mL·h)
300
200 150
15
10
100
Single-dose AUC0–inf Multiple-dose AUCtau,ss
50
Single-dose: Cmax Multiple-dose: Cmax,ss
5
0
0 0
100 200 300 400 500 600 700 800 900 Lacosamide dose (mg)
0
100 200 300 400 500 600 700 800 900 Lacosamide dose (mg)
Linear regression based on the arithmetic means from the individual studies
Figure 1. LCM AUC and Cmax in healthy subjects following single or multiple oral dosing (linear regression based on the arithmetic means ± SD). The approved daily dose for adjunctive LCM is up to 400 mg/day (200 mg BID). AUC, area under the concentration time curve; Cmax , peak plasma concentration; LCM, lacosamide; SD, standard deviation.
tract with peak plasma concentrations (Cmax ) occurring about 0.5–4 h postdose in healthy subjects.26 Study in healthy subjects has shown that the rate and extent of LCM gastrointestinal absorption are not altered by food intake,40 thereby simplifying the dosing regimen of a patient allowing administration irrespective of meals. Following oral administration, LCM shows linear pharmacokinetics (Fig. 1) that are constant over time, with low intra- and intersubject variability.25,26,30 LCM pharmacokinetic parameters were generally consistent between healthy subjects (Table 1) and adults with focal epilepsy (Table 2). Distribution The volume of distribution (Vd) of LCM is 0.6 L/kg, which is close to the volume of the total body water.25,26 The low plasma protein binding ( CLCR 50 mL/min) Moderate (50 mL/min > CLCR 30 mL/min) Severe (CLCR 20–30 mL/min or < 20 mL/min) ESRD (no hemodialysis; CLCR < 15 mL/min) ESRD (hemodialysis; CLCR < 15 mL/min) Korean subjects Kim et al.57
Drug interaction studies Carbamazepine Cawello et al.37
Valproic acid
Cawello et al.34
Application Tablet 15 min IV Tablet 30 min IV 60 min IV Tablet Oral solution Oral solution 60 min IV
Tablet
No. subjects
Dose (mg)
16 16 23 24 25 16 16 5 5
200 (2 × 100 mg) 200 (200 mg/20 mL) 200 (2 × 100 mg) 200 (200 mg/20 mL) 200 (200 mg/20 mL) 200 (2 × 100 mg) 200 (200 mg/mL) 100 (100 mg/5 mL) 100 (100 mg/40 mL)
8
100
Single Single Single Single Single Single Single Single Single
4.76 (23.6) 5.72 (36.3) 4.93 (27.9) 5.76 (28.0) 5.26 (22.5) 5.26 (19.8) 5.14 (16.5) 3.36 (0.603)c 3.38 (0.327)c
0.75 (0.28–4.0)b 0.25 (0.25–2.0)b 0.75 (0.25–4.0)b 0.5 (0.5–2.0)b 1.0 (1.0–3.0)b 1.0 (0.5–1.5)b 0.5 (0.5–2.0)b 0.60 (0.22)c 1.30 (0.45)c
76.50 (18.4) 75.40 (17.0) 79.54 (24.9) 79.84 (24.6) 80.53 (25.6) 84.51 (22.2) 83.31 (21.8) 62.20 (10.0)c 71.8 (7.0)c
13 (10.1–16.2)b 12.6 (10.8–16.1)b 11.2 (9.3–18.0)b 11.4 (9.3–17.0)b 11.3 (9.5–17.2)b 12.5 (19.1) 12.4 (18.3) 15.0 (3.27)c 16.3 (2.03)c
Single
2.69 (35.0)
1.00 (0.5–2.0)b
47.01 (20.8)
13.2 (17.6)
59.62 (17.5)
18.2 (18.7)
t1/2 (h)
Tablet
8
100
Single
2.95 (20.7)
Tablet
8
100
Single
3.06 (10.0)
0.50 (0.5–1.0)b
57.57 (19.0)
15.4 (18.9)
Tablet
8
100
Single
3.02 (23.3)
1.00 (0.5–1.5)b
74.76 (26.9)
18.3 (27.8)
Tablet
8
100
Single
3.18 (22.4)
0.50 (0.5–4.0)b
73.37 (26.3)
19.6 (19.4)
Tablet
8
100
Single
2.79 (22.1)
0.70 (0.5–2.0)b NA
19.2 (26.8)
Tablet Tablet Tablet Tablet Tablet
12 12 12 12 12
50 100 200 100 BID 200 BID
0.5 (0.5–1.5)b 27.55 (15.1) 0.75 (0.5–2.0)b 52.71 (14.4) 1.5 (0.5–4.0)b 116.69 (16.5) 52.10 (17.0) 0.5 (0.5–2.0)b 0.5 (0.50–1.0)b 112.35 (13.0)
15.3 (12.0) 15.0 (16.5) 15.9 (12.4) 16.0 (14.6) 16.7 (11.7)
Tablet
19
200 mg BID
2.2 (0.9)c
83.3 (14.0)c
12.8 (1.4) (n = 9)
Tablet
18
200 mg BID
2.4 (1.0)c
79.7 (13.4)c
Capsule
16
200 mg BID
0.8 (0.5–3.0)b
82.9 (13.8)c
Capsule
15
200 mg BID
0.5 (0.5–1.0)b
82.7 (13.9)c
0.93 (0.61)c
83.2 (11.4)c
12.8 (2.0) (n = 10) 13.2 (10.7–18.7) (n = 8)b 15.6 (10.7–19.1) (n = 7)b —
Cawello et al.35
Tablet
20
200 mg BID
Omeprazole
Cawello et al.36
Tablet
34
300
Tablet
34
300
Tablet
31
200 mg BID
Cawello et al.54
tmax a (h)
0.50 (0.5–1.0)b
Digoxin
R Microgynon
AUCa (g/mL h)
Cmax a (g/mL)
Dosing schedule
Single Single Single Multiple Multiple
1.63 (9.1) 2.85 (14.6) 5.84 (24.3) 6.23 (15.0) 13.13 (8.9)
Multiple 9.9 (2.0)c (LCM + CBZ) Multiple 9.1 (1.6)c LCM alone Multiple 9.7 (1.2)c LCM + VPA Multiple 9.5 (1.3)c LCM alone Multiple 9.5 (1.1)c LCM + digoxin Single 7.335 (16.9) LCM + OMZ Single 7.366 (19.8) LCM alone Multiple 13.8 (2.2)c LCM + microgynon
1.00 (0.5–3.0)b 160.3 (22.4)
16.2 (13.5)
1.00 (0.5–3.0)b 134.0 (22.1)
13.2 (12.7)
1.1 (0.4)c
15.3 (2.0)c
113.5 (20.7)c
a
tmax , Cmax , and AUC represent values after single dose or steady state after multiple twice-daily dosing. Median (range). c Arithmetic mean ± standard deviation. AUC, area under the curve; BID, twice daily; Cmax , maximum plasma concentration; CBZ, carbamazepine; CLCR , creatinine clearance; ESRD, end-stage renal disease; IV, intravenous infusion; LCM, lacosamide; NA, not available; OMZ, omeprazole; tmax , time to maximum plasma concentration; t1/2 , half-life; VPA, valproic acid. b
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Table 2. Summary of adjunctive LCM pharmacokinetics at end of maintenance in adults with focal epilepsy
Mean plasma concentration (g/mL) (SD)
Ctrough (g/mL) (SD)
4.99 (2.51) 9.35 (4.22) 12.46 (5.80)
NA NA NA
Application
No. of subjectsa
Dose (mg/day)
Dosing schedule
Ben-Menachen et al.
Tablet Tablet Tablet
85 83 61
200 400 600
Multiple
Haslaz et al.29
Tablet Tablet
163a 159a
200 400
Multiple
3.8b 7.4b
NA NA
Chung et al.28
Tablet Tablet
204a 97a
400 600
Multiple
7.19b 9.5b
NA NA
Krauss et al.56
IV infusion IV infusion IV infusion
14 25 17
200 400 600
Multiple
Fountain et al.55
Loading IV Loading IV Loading IV
25 50 25
200c 300c 400c
Single
Study 27
5.5 (1.2) 10.5 (2.5) 15.9 (4.1) 6.59 (2.22) 9.32 (3.77) 12.33 (4.12)
2.6 (0.8) 4.7 (1.4) 7.7 (2.7) NA NA NA
a
Patients randomized to LCM. Standard deviation not provided. c Single dose in mg. All values are mean (SD), unless otherwise indicated. IV, intravenous infusion; NA, not available; LCM, lacosamide; SD, standard deviation. b
levels of metabolites. Finally, drug-metabolizing enzymes can be affected by genetic mutations resulting in increased, decreased, or suppressed activity, and the incidence of such mutations can differ substantially (from rare to frequent) among different ethnic groups. Thus, knowledge of the enzymatic pathways involved in drug metabolism, and whether the drug may induce or inhibit such enzymes, can help the clinician provide optimal therapy and avoid potential drug interactions.49 Following oral or intravenous (IV) administration of 100 mg (40 Ci) [14 C]-LCM in healthy subjects, the majority of the radioactivity in plasma was found to be unchanged LCM (61–71% after oral administration; 71–81% after IV infusion).30 LCM is metabolized primarily via demethylation to the O-desmethyl metabolite (elimination halflife 15–23 h), which has no known pharmacological activity.30,50,51 The plasma exposure of O-desmethyl-lacosamide is approximately 10–15% that of LCM.25,26 The metabolic profile of LCM remains similar following oral administration or IV infusion, suggesting no first-pass effect following oral administration.30
22
Studies have suggested CYP2C19 as the main CYP isoform implicated in the demethylation of LCM. In addition to CYP2C19, in vitro data indicated that CYP3A4 and CYP2C9 catalyze the formation of the LCM O-desmethyl metabolite.25,26 The metabolism of LCM by three CYP isozymes reduces the likelihood of drug interactions because the metabolism of the drug is not dependent on one specific CYP pathway. In healthy male or female subjects, no clinically relevant changes in plasma concentrations (based on Cmax and AUC) have been observed when LCM was coadministered with CYP substrates and inducers, such as midazolam (CYP3A4), or inhibitors, such as omeprazole (CYP2C19).36,52 LCM plasma concentrations were similar between CYP2C19 poor and extensive metabolizers; however, plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were reduced by 70% in CYP2C19 poor metabolizers compared to the extensive metabolizers.25 In addition, coadministration of a CYP2C19 substrate and inhibitor, omeprazole, reduced the formation of O-desmethyl-lacosamide by approximately 60%.36
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These two studies indicate the involvement of CYP2C19 in the demethylation of LCM. Elimination LCM is eliminated primarily by the kidneys, with less than 1% of the dose eliminated by the feces.26,30 Following oral or IV administration of [14 C]-LCM in healthy subjects, the total radioactivity was excreted relatively quickly, with a mean of 82% of the administered dose excreted within 48 h and approximately 95% excreted within 168 h postdose, indicating no accumulation of unchanged LCM or its metabolites in red blood cells or other tissues.26,30 Apparent plasma clearance (CL/F) in healthy subjects and patients with focal epilepsy (and in all aspects of consideration, e.g., ethnicity, symptoms like decreased renal function as well as coadministration of other drugs) was between 1.34 and 2.65 L/h.36,53,54 The cumulative urinary excretion consisted mainly of unchanged LCM (40% of a dose), the primary metabolite, O-desmethyl-lacosamide (30%), and a polar fraction of compound(s) not further identified (20%).30,51 Additional metabolites were identified only in small amounts ( 30 mL/min), and 100 mg (followed by 50 mg BID regimen in the first 7 days) in patients with severe renal impairment (CLCR 30 mL/min) may be considered, but further dose titration should likewise be performed with caution. 26 At the time of this writing, a loading dose of LCM is not indicated for use in the United States. In addition, LCM exposure may be increased in patients with
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renal impairment who are taking strong CYP3A4 and CYP2C9 inhibitors; LCM dose reduction may be necessary in these patients.25 Hemodialysis significantly affects systemic LCM exposure. In patients with ESRD, the mean extraction rate of LCM during hemodialysis was 57%.53 More specifically, after a single 100 mg oral dose of LCM, exposure (based on AUC) was 50% lower in patients receiving hemodialysis versus dosing on a hemodialysis-free day. Therefore, LCM dosage supplementation up to 50% of the divided daily dose directly after the end of hemodialysis should be considered.25,26 Although it has not been used in the few known cases, standard hemodialysis may result in a 50% reduction of systemic LCM exposure in 4 h and may be indicated in the event of LCM overdose.25 Patients with hepatic impairment Subjects with moderate hepatic impairment (ChildPugh B) on steady-state LCM (200 mg/day for 4.5 days) showed increases in LCM exposure (based on AUCss ) of 50–60% compared with healthy controls.25,26 Based on this, a maximum dose of 300 mg/day is recommended in the United States for patients with mild or moderate hepatic impairment.25 The higher exposure in subjects with moderate hepatic impairment was caused in large part to reduced renal function in these subjects compared with healthy controls as the decrease in nonrenal clearance in the subjects was estimated to give a 20% increase in the AUC of LCM.26 Based on this, in Europe no dose adjustment is recommended in patients with mild or moderate hepatic impairment.26 Recommendations in Europe for use of LCM as a single loading dose in patients with hepatic impairment are similar to those discussed above for patients with mild/moderate renal impairment; a single loading dose of 200 mg may be considered, with any further dose titration then performed with caution.26 It should also be noted that pharmacokinetics of LCM have not been systematically evaluated in patients with severe hepatic disease, and as a result the use of LCM in patients with severe hepatic impairment is not recommended. Significant increases in LCM exposure may occur in patients with hepatic impairment who are taking strong CYP3A4 and CYP2C9 inhibitors. LCM dose reduction may be necessary in these patients.25
Lacosamide pharmacokinetics
Drug–drug interactions Many factors contribute to an increased likelihood of drug–drug interactions, including extensive metabolism, the capacity to induce or inhibit enzymes involved in drug metabolism, formation of active metabolites, and high plasma protein binding. For AEDs, the risk of drug–drug interactions is highlighted mainly by older AEDs, most of which are known inducers or inhibitors of drug metabolizing enzymes.65,66 In vitro studies suggested that, at clinically relevant concentrations observed in clinical studies, LCM did not induce the activity of CYP isoforms 1A2, 2B6, 2C9, 2C19, or 3A4 or inhibit the activity of CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, or 3A4/5.25,26 In vitro data suggest, however, that LCM is a substrate for and moderate inhibitor of CYP2C19.30,50 These results suggest that LCM should not affect the metabolism of drugs undergoing CYP-mediated biotransformation. A number of in vivo drug–drug interaction studies have been conducted to assess the potential of LCM to interact with commonly used AEDs and other therapeutic agents, both in healthy subjects and in patients with focal epilepsy. These studies have demonstrated that LCM has a low potential for clinically relevant pharmacokinetic drug–drug interactions. AEDs Drug–drug interaction–specific studies conducted in healthy male subjects found that administration of LCM (200 mg BID) does not affect the pharmacokinetics of carbamazepine (CBZ; 200 mg BID) or valproic acid (VPA; 300 mg BID) and that CBZ and VPA do not affect the pharmacokinetics of LCM, based on AUC and Cmax at steady state (Table 1).34,37 Data pooled from phase III placebo-controlled studies in adults with focal epilepsy have shown that LCM does not affect the plasma concentration of concomitantly administered AEDs, including levetiracetam, carbamazepine and carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide.26 A separate population pharmacokinetic analysis showed small (15–20%) reductions in LCM plasma concentrations when LCM was coadministered with enzyme-inducing AEDs, such as carbamazepine, phenobarbital, or phenytoin.25
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However, no dose adjustment is required in patients on concomitant enzyme-inducing AEDs. The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system. LCM has been shown to cause dose-related prolongation of the PR interval,25,26 and conduction abnormalities have been associated with carbamazepine treatment.67 A multiple-dose, open-label study evaluating the interaction between LCM and carbamazepine in healthy male patients did not demonstrate an increased magnitude of PR prolongation.37 Further, an increased magnitude of PR prolongation in patients treated with LCM and concomitant carbamazepine or lamotrigine was not identified in a clinical study subgroup analysis.26 LCM should be used with caution in patients with known conduction problems (e.g., marked first-degree atrioventricular block, second-degree or higher atrioventricular block and sick sinus syndrome without pacemaker, sodium channelopathies (Brugada Syndrome), on concomitant medications that prolong PR interval, or with severe cardiac disease such as myocardial ischemia or heart failure, or structural heart disease). In such patients, obtaining an ECG before beginning LCM, and after LCM is titrated to steady state, is recommended.25 Other (non-AED) drug–drug interaction studies in healthy subjects Warfarin. Warfarin has a narrow therapeutic index (optimal international normalized ratio (INR) 2–3),68 and plasma levels outside the therapeutic range may lead to increased risk of thrombotic events or bleeding.69 Warfarin is a mixture of enantiomers in which the R-enantiomer is primarily metabolized by CYP1A2 and 3A4 and the S-enantiomer by CYP2C9.70 Drugs that compete as substrates or inhibit the activity of these CYP isoforms may increase warfarin plasma concentrations, potentially increasing the risk of bleeding.70 Coadministration of LCM (400 mg/day (200 mg BID)) did not alter the pharmacokinetics of warfarin (25 mg), as the mean plasma concentration–time profiles for the warfarin S- and R-enantiomers remained unchanged following LCM coadministration.38 The level of anticoagulation in subjects receiving warfarin was also shown to be unaffected by concomitant intake of 28
LCM. These results suggest that there is no need for dose adjustment of warfarin when coadministered with LCM.38 Digoxin. Digoxin metabolism is independent of the CYP450 system, and digoxin is not known to induce or inhibit CYP isozymes.71 Digoxin is, however, a P-glycoprotein substrate and dependent on the glycoprotein for intestinal absorption and renal elimination.72 Because of digoxin’s dependency on P-glycoprotein, digoxin has become the standard for evaluating P-glycoprotein–mediated potential drug–drug interactions.72 Digoxin has a narrow therapeutic window, and small changes in exposure may decrease efficacy or increase toxicity.73 Coadministration of digoxin (0.25 mg/day) with LCM (400 mg/day; multiple doses) versus digoxin alone revealed no differences in digoxin exposure.35 These results suggest that LCM would not be expected to affect the disposition of P-glycoprotein substrates.35 A small increase was noted in the PR interval for coadministered digoxin plus LCM compared with either drug administered alone. LCM should be used with caution in patients treated with products known to be associated with PR prolongation and in patients treated with class 1 antiarrhythmics.25,26 Omeprazole. Omeprazole is a proton-pump inhibitor that is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4. Therefore, drugs that affect the activity of these CYP isozymes, particularly CYP2C19, may influence the metabolism of omeprazole.74 Omeprazole also acts as a CYP2C19 inhibitor, and may affect the metabolism of drugs metabolized by this enzyme.74 In healthy male subjects with normal CYP2C19 activity, multiple-dose LCM (200 mg BID) administration (at steady state) did not affect the pharmacokinetics of single-dose omeprazole (40 mg). Multiple-dose omeprazole administration (40 mg/day) did not influence LCM single-dose (300 mg) pharmacokinetics (Table 1).36 These data suggest that LCM exposure is unlikely to be affected to a clinically relevant extent by moderate CYP2C19 inhibitors. However, caution is recommended when LCM is coadministered with strong CYP2C9 inhibitors (e.g., fluconazole).26 Although omeprazole did not significantly affect the pharmacokinetics of LCM, formation of O-desmethyllacosamide was reduced (60%) with omeprazole coadministration, supporting that CYP2C19 is the
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main CYP isoform involved in the demethylation of LCM.36 Midazolam. Midazolam is mainly metabolized by CYP3A4.75 Midazolam has been used as a test substrate to assess the effect of drugs on the activity of 3A4.76 In healthy subjects, single (200 mg) and multiple doses (400 mg/day) of LCM did not affect the metabolism of a single dose (7.5 mg) of midazolam. In addition, the AUC confidence intervals for all treatments fell within the accepted 80–125% bioequivalence range.52 However, the midazolam Cmax was slightly elevated (30%) when coadministered with 400 mg (200 mg BID) LCM.26 The in vivo data therefore support that no clinically relevant induction or inhibition of CYP34A by LCM occurs at clinically relevant doses in healthy subjects. Combined oral contraceptive (OC). The combined OC contains a progestin (e.g., levonorgestrel or norethindrone) and an estrogen (usually ethinylestradiol), both of which are metabolized by CYP enzymes.77 Several AEDs, including older (carbamazepine, phenytoin, phenobarbital, and primidone) and newer AEDs (oxcarbazepine, topiramate (>200 mg), and eslicarbazepine acetate) are CYP3A4 enzyme inducers and may reduce the plasma concentrations of OC, and therefore have the potential to compromise contraception.66 Moreover, many women with epilepsy are unaware of these potential interactions that may lead to contraceptive failure.78 It is therefore important to define the potential for interaction between contraceptives and AEDs in order to optimize effective treatment plans for women of child-bearing age with epilepsy. In an open-label study in healthy female subjects, no pharmacokinetic interaction was observed between LCM (400 mg/day) and the combined OC containing ethinylestradiol (0.03 mg) plus levonorgestrel (0.15 mg).54 The study found the same level of progesterone suppression (
