The pharmacokinetic, safety, and tolerability profiles of eslicarbazepine acetate are comparable between Korean and White subjects

A post hoc analysis of data from Asian patients included in the study BIA‐2093‐304 was conducted to evaluate the long‐term safety/tolerability and efficacy of adjunctive eslicarbazepine acetate (ESL) in adult Asian patients with refractory focal seizures. Part I was a randomized controlled trial, in which patients received ESL (800 or 1200 mg once daily [QD]) or placebo, assessed over a 12‐week maintenance period. Patients completing Part I could enter two open‐label extension periods (Part II, 1 year; Part III, ≥2 years), during which all received ESL (400–1600 mg QD). Safety/tolerability was assessed by evaluating treatment‐emergent adverse events (TEAEs). Efficacy assessments included responder and seizure freedom rates. The safety population included 125, 92, and 23 Asian patients in Parts I, II, and III, respectively. Incidence of ESL‐related TEAEs was 61.3%, 45.7%, and 17.4% during Parts I, II, and III, respectively. ESL‐related TEAEs (most commonly, dizziness, somnolence, and headache) were consistent with ESL's known safety profile. During Part I, responder rates were higher with ESL 800 (41.7%) and 1200 mg QD (44.4%) versus placebo (32.6%), although not statistically significant. Seizure freedom rates with ESL 800 (5.5%) and 1200 mg QD (11.1%) were also higher versus placebo (0%) (p < 0.05 for ESL 1200 mg QD versus placebo). At the end of Part II, responder and seizure freedom rates were 60.3% and 14.7%, respectively. In summary, adult Asian patients with refractory focal seizures were responsive to treatment with ESL as adjunctive therapy and generally showed treatment tolerance well for up to 3 years. No new/unexpected safety findings were observed.

Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Long‐term effects of adjunctive eslicarbazepine acetate in adult Asian patients with refractory focal seizures: Post hoc analysis of a phase III trial

Lee,

Hong

et al. 2024

The pharmacokinetic, safety, and tolerability profiles of eslicarbazepine acetate are comparable between Korean and White subjects

Hwang

Lee

Kim

et al. 2022

Eslicarbazepine acetate (ESL) is a prodrug antiseizure medication for the treatment of focal seizures. ESL shows a well‐established pharmacokinetic (PK)‐pharmacodynamic relationship and has similar extrinsic epilepsy‐related factors across ethnicities. This study evaluated and compared ESL safety, tolerability, and PK characteristics between Korean and White subjects. A randomized, double‐blind, placebo‐controlled, single‐ and multiple‐dose escalation study was conducted in healthy Korean and White adults. Participants randomly received a single dose and multiple oral doses of ESL (400–1600 mg) or placebo once daily for 11 days at a ratio of 8:2. Serial blood samples were collected to determine the plasma concentration of ESL and its metabolites (eslicarbazepine, [R‐licarbazepine and oxcarbazepine). Safety and tolerability were assessed throughout the study. A total of 29 Korean and 20 White subjects completed the study. The PK profiles of the metabolites of ESL were similar between Korean and White subjects. The geometric mean ratio (90% confidence interval) of Korean to White subjects for the area under the concentration–time curve within a dosing interval of eslicarbazepine was 1.06 (0.97–1.17) and 0.96 (0.87–1.06) after multiple oral doses of 400 and 1600 mg ESL, respectively. Other PK parameters were also similar between the two ethnic groups. ESL was well‐tolerated in healthy Korean and White subjects, and its PK characteristics were similar between the two ethnic groups. The results of this study support to use the same dosage regimen of ESL in both White and Korean patients with seizures.

Pharmacokinetic drug–drug interactions of JBPOS0101 mediated by cytochrome P450 3A4 and UDP‐glucuronosyltransferases

Hwang,

Choi,

Kim

et al. 2024

Self Cite

JBPOS0101 is a new antiepileptic drug and is a substrate of UDP‐glucuronosyltransferases (UGTs) in in vitro test. In vitro experiments showed different results regarding whether JBPOS0101 induces (EC50 136 μM) or inhibits (IC50 95.4–386.5 μM) cytochrome P450 (CYP) 3A4. As co‐medication of JBPOS0101 and carbamazepine (CBZ) is expected in clinical settings, drug–drug interactions (DDIs) between them should be determined. This study aimed to investigate pharmacokinetic (PK) interactions of JBPOS0101 influenced by CYP3A4 and UGTs using midazolam (MDZ) and CBZ. A two‐cohort, open‐label, fixed‐sequence study was conducted in healthy Koreans. In cohort A, subjects received MDZ IV alone, and then JBPOS0101 were co‐administered with MDZ after oral doses of JBPOS0101 for 7 days. In cohort B, multiple doses of JBPOS0101 and CBZ were administered respectively, and subjects received both together for 7 days. Serial blood samples were collected for PK analysis. When MDZ and JBPOS0101 were co‐administered, the systemic exposure of MDZ decreased by 30%. Meanwhile, JBPOS0101 did not significantly changed the PK of CBZ. CBZ decreased the systemic exposure of JBPOS0101 at steady state by 40%, respectively. With IV administration of MDZ, JBPOS0101 acted as a weak inducer of hepatic CYP3A4 and decreased systemic exposure of MDZ. The ability of JBPOS0101 to similarly modulate gut CYP3A4 activity will require further evaluation. Co‐administration of multiple doses of JBPOS0101 and CBZ did not significantly alter CBZ pharmacokinetics, but the clinical impact of decreased systemic exposure of JBPOS0101 by CBZ should be further considered.