Adolescent Clinical Development of Ezogabine/Retigabine as Adjunctive Therapy for Partial-Onset Seizures: Pharmacokinetics and Tolerability

Abstract

OBJECTIVES: To explore the pharmacokinetic (PK) profile and safety of ezogabine (EZG)/retigabine (RTG) as adjunctive therapy for uncontrolled partial-onset seizures (POS) in adolescents. METHODS: In this multiple-dose study (NCT01494584), adolescents with POS received EZG/RTG immediate-release tablets three times daily (TID) as adjunctive therapy to 1 to 3 concurrent antiepileptic drugs. The study comprised a screening phase, and a 5- to 8-week treatment phase starting with 100 mg TID up-titrated once weekly by ≤50 mg TID to a maximum dosage of 300 mg TID. There were 8 venous blood samples and 2 finger-prick blood samples collected for PK analysis during 8-hour time periods at the target dosages of 100, 200, and 300 mg TID. RESULTS: This study was terminated prematurely on US Food and Drug Administration advice due to pigmentation/discoloration findings in long-term, open-label extension studies in adults. Five participants (ages 13-16 years) had enrolled in the study. For the EZG/RTG 100-, 200-, and 300-mg doses, the area under the concentration-time curve during the dosage intervals was 1680, 2559, and 3784 ng/hr/mL; maximum plasma concentrations were 370, 536, and 751 ng/mL, and minimum plasma concentrations were 105, 200, and 287 ng/mL, respectively. Venous and finger-prick concentrations of EZG/RTG were similar. No significant adverse events were observed during treatment (133-213 days). CONCLUSIONS: EZG/RTG PK appeared linear across the dosage range of 100 to 300 mg TID in adolescents with POS, and were consistent with adult observations. The small sample size and short study duration preclude conclusions regarding the safety and efficacy of EZG/RTG.

Keywords: adolescent; anticonvulsant; antiepileptic drug; epilepsy; ezogabine; pharmacokinetics; retigabine; seizures.

Figures

Figure 1.

Mean plasma ezogabine/retigabine (EZG/RTG) concentration–time plots by EZG/RTG daily dosage. 300 mg (100 mg TID); 600 mg (200 mg TID); 900 mg (300 mg TID)

Figure 2.

Comparison of ezogabine/retigabine (EZG/RTG) concentrations in blood samples collected by standard EZG/RTG venous sampling and finger-prick sampling. TID, three times daily. EZG/RTG 300 mg (100 mg TID) (n=4); EZG/RTG 600 mg (200 mg TID) (n=3); • EZG/RTG 900 mg (300 mg TID) (n=4); Line of unity representing no difference between the values for EZG/RTG concentration obtained by venous and finger-prick sampling.

Figure 3.

Ezogabine/retigabine (EZG/RTG) area under the concentration-time curve from time zero (predose) to 8 hours postdose (AUC(0-8)) values in adolescent participants compared with adult participants by EZG/RTG daily dosage 100 mg, 200 mg, and 300 mg three times daily (TID). ⋄ Adolescent AUC(0–8); ○ Median Adult; ▭ Minimum/Maximum