PII-055 - A RANDOMIZED, THREE-PERIOD, CROSSOVER STUDY OF SINGLE AND REPEATED DOSES OF ELIGLUSTAT IN HEALTHY PARTICIPANTS, CYP2D6 EXTENSIVE AND POOR METABOLIZERS

C. Xu¹, S. Macha¹; ¹Sanofi, NJ, USA.

Background: A Phase 1, randomized, three-period, crossover study of single and repeated doses of three different strengths of eliglustat was conducted in healthy participants with CYP2D6 extensive and poor metabolizers (EM and PM). The primary objective was to evaluate dose proportionality at three different doses of eliglustat after single and repeated (BID for EMs and QD for PMs) oral administration.

Methods: Male or female participants between 18 and 65 years of age participated in the study (11 EM, 7 PM). Participants received 21, 42, and 84 mg doses of eliglustat capsules. A 7- to 10-day wash-out period was implemented between treatment periods. In each treatment period, serial pharmacokinetic (PK) samples were collected up to 12 hours (for the BID regimen) or 24 hours (for the QD regimen) after the first dose on Day 1 and at the steady state on Day 7. The pharmacokinetic parameters were calculated using non-compartmental analysis from plasma eliglustat concentrations and were summarized using descriptive statistics.

Results: In healthy CYP2D6 EM participants, eliglustat AUC increased more than dose proportionally with a 5.3 to 6.5-fold increase in AUC over the 4-fold dose range from 21 to 84 mg after single and repeated BID doses. Cmax increased approximately dose proportionally after single doses but more than dose proportionally after repeated doses (6.7-fold increase over the 4-fold dose range from 21 to 84 mg). In healthy CYP2D6 PM participants, dose proportional increase in eliglustat plasma exposures was observed over the 4-fold dose range from 21 to 84 mg eliglustat after single and repeated QD doses. In addition, for all three doses in both CYP2D6 EM and PM participants, eliglustat concentrations appeared to reach steady state by Day 4.

Conclusion: Eliglustat PK were characterized in CYP2D6 EM and PM participants at three different doses of eliglustat after single and repeated dosing. These results further delineated eliglustat PK in CYP2D6 EM and PM participants to supplement the current understanding on eliglustat metabolism. Eliglustat is both a substrate and inhibitor of CYP2D6 and thus leads to auto-inhibition of eliglustat metabolism in CYP2D6 EM participants but not in CYP2D6 PM participants who have no functional CYP2D6.