title: Changes in hormone and lipid levels in male patients with focal seizures when switched from carbamazepine to lacosamide as adjunctive treatment to levetiracetam: A small phase IIIb, prospective, multicenter, open-label trial.
abstract: Treatment with enzyme-inducing antiepileptic drugs (AEDs) such as carbamazepine (CBZ) can lead to changes in reproductive, endocrine, and lipid parameters, resulting in clinical symptoms for some patients. Previous studies indicate that these changes can be reversed by switching to a nonenzyme-inducing AED. Lacosamide is a newer-generation AED, not known to induce or strongly inhibit cytochrome P450 (CYP450) enzymes. In this phase IIIb, prospective, multicenter, open-label, single-arm trial (NCT01375374), the serum concentrations of CYP-related reproductive hormones, thyroid hormones, and lipids were assessed in otherwise healthy male patients with focal seizures (N=11), before and after a switch from CBZ (600-1200mg/day at baseline) to lacosamide (target dose: 400mg/day by the end of titration) as adjunctive treatment to the nonenzyme-inducing AED levetiracetam (LEV, stable dosage of >1000mg/day throughout). Cross titration took place over 4weeks, followed by an 8-week maintenance period. Serum measurements were conducted at baseline and at the end of maintenance. The median serum sex-hormone-binding globulin (SHBG) concentration was towards the higher end of the normal range at baseline and decreased following the switch (61.7 to 47.5nmol/L, N=10, p=0.027 by Wilcoxon signed-rank test). Free androgen index (100×testosterone/SHBG) and free thyroxine serum concentration increased (25.4 to 36.4 and 13.0 to 14.9pmol/L, respectively, both N=10 and p=0.002). At baseline, the median progesterone serum concentration was below the normal range (0.7nmol/L), whereas median cholesterol and low-density lipoprotein concentrations were above the normal range (5.5 and 3.6mmol/L, respectively). By the end of maintenance, all measured parameters were within the normal range. The safety and tolerability profile of lacosamide was consistent with that observed in previous studies. Furthermore, antiseizure efficacy appeared to be maintained, suggesting that deinduction of CYP enzymes following a switch from CBZ to lacosamide as adjunctive therapy to LEV is feasible within 8weeks and is associated with normalization of serum parameters.
authors.affiliation: Department of Epileptology, University of Bonn, Sigmund Freud Str. 26, Bonn 53015, Germany. Electronic address: christian.elger@ukb.uni-bonn.de.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Elger
authors.affiliation: Department of Epileptology, University of Bonn, Sigmund Freud Str. 26, Bonn 53015, Germany. Electronic address: michael.rademacher@ukb.uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Rademacher
authors.affiliation: Krankenhaus Mara, Epilepsiezentrum Bethel, Bielfeld, Germany. Electronic address: christian.brandt@mara.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Brandt
authors.affiliation: UCB Pharma, Raleigh, NC, USA. Electronic address: sami.elmoufti@ucb.com.
authors.forename: Sami
authors.initials: S
authors.lastname: Elmoufti
authors.affiliation: UCB Pharma, Brussels, Belgium. Electronic address: peter.dedeken@ucb.com.
authors.forename: Peter
authors.initials: P
authors.lastname: Dedeken
authors.affiliation: UCB Pharma, Monheim-am-Rhein, Germany. Electronic address: klaus.eckhardt@ucb.com.
authors.forename: Klaus
authors.initials: K
authors.lastname: Eckhardt
authors.affiliation: UCB Pharma, Monheim-am-Rhein, Germany. Electronic address: frank.tennigkeit@ucb.com.
authors.forename: Frank
authors.initials: F
authors.lastname: Tennigkeit
authors.affiliation: UCB Pharma, Brussels, Belgium. Electronic address: marc.debacker@ucb.com.
authors.forename: Marc
authors.initials: M
authors.lastname: De Backer
mesh_terms: D000081:Acetamides / Q000627:therapeutic use; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D004828:Epilepsies, Partial / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D000078334:Lacosamide; D000077287:Levetiracetam; D008055:Lipids / Q000097:blood*; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D010889:Piracetam / Q000031:analogs & derivatives / Q000627:therapeutic use; D011374:Progesterone / Q000097:blood*; D011446:Prospective Studies; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D013739:Testosterone / Q000097:blood*; D013974:Thyroxine / Q000097:blood*; D016896:Treatment Outcome
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D008055:Lipids; D008077:Lipoproteins, LDL; D012738:Sex Hormone-Binding Globulin; D002220:Carbamazepine; D013739:Testosterone; D000077287:Levetiracetam; D011374:Progesterone; D000078334:Lacosamide; D002784:Cholesterol; D013974:Thyroxine; D010889:Piracetam
keywords: Androgens; Antiepileptic drugs; CYP enzymes; Cholesterol; Enzyme-inducing drugs; Thyroid