Sabril Vision Study: Pharmacokinetic and Pharmacodynamic Analysis of the Effect of Vigabatrin on Taurine Plasma Concentrations (P2.026)

Objective: Explore the relationship between vigabatrin plasma concentrations and (1) vision endpoints (Humphrey field analyzer [HFA] and retinal nerve fiber layer [RNFL]), and (2) taurine plasma concentrations. The relationship between taurine plasma concentrations and HFA and RNFL also was explored. Background: Taurine is a naturally occurring amino acid that is essential for normal development and function of retinal rod photoreceptors. Reports suggest vigabatrin treatment may cause taurine deficiency in mice and humans. Methods: The vision study was a prospective, longitudinal, single-arm, open-label study (NCT01278173). Eligible vigabatrin-nave adult patients (≥2 seizures/month who failed ≥3 therapies) performed reliable perimetry (Humphrey automated static) and retinal-structure assessment (spectral-domain optical coherence tomography) pre-vigabatrin exposure. Following vigabatrin initiation, vision testing occurred within 1 month (reference) and at 3, 6, 9, and 12 months. Sparse pharmacokinetic sampling to measure plasma concentrations of vigabatrin and taurine were performed during the study. The relationships between vigabatrin plasma concentrations and HFA and RNFL (change from reference), and taurine plasma concentrations, as well as taurine plasma concentrations on HFA and RNFL, were evaluated through mixed-effect analysis. Results: Sixty-five of 91 screened patients received ≥1 vigabatrin dose (all-patients-treated set [APTS]); 38 (59[percnt]) APTS patients completed the study. Fifty-three patients from the APTS had at least one quantifiable vigabatrin plasma concentration measurement (PK population). No relationship was found between vigabatrin plasma concentrations and HFA and RNFL. A small but significant relationship (P<0.01) with vigabatrin plasma concentrations and taurine plasma concentrations (time-independent) was identified; taurine plasma concentrations decreased with increasing vigabatrin plasma concentrations. No relationship was observed between plasma taurine concentrations and HFA and RNFL. Conclusions: Although concentrations of taurine in plasma decreased with increasing plasma vigabatrin concentrations, no relationship was found between plasma concentrations of vigabatrin or taurine and HFA and RNFL. Funding: Lundbeck, LLC Disclosure: Dr. Tolbert has received personal compensation for activities with Lundbeck LLC. Dr. Timmermann has received personal compensation for activities with Lundbeck LLC. Dr. Areberb has received personal compensation for activities with Lundbeck LLC. Dr. Lee has received personal compensation for activities with Lundbeck as an employee. Dr. Whittle has received personal compensation for activities with Lundbeck LLC.