PII-089 - THE EFFECTS OF CYP3A INDUCTION AND INHIBITION ON ZURANOLONE PHARMACOKINETICS IN HEALTHY ADULTS.

J. Dunbar, N. Srinivas, E. Hoffmann; Sage Therapeutics, Inc., Cambridge, MA, USA.

Background: Zuranolone (ZRN) is positive allosteric modulator of synaptic and extrasynaptic GABAa receptors and a neuroactive steroid in development as an oral, once-daily, 14-day treatment course for adults with major depressive disorder and postpartum depression. ZRN is extensively metabolized, including contributions from CYP3A. This study was conducted to evaluate the effects of rifampin (RIF) and itraconazole (ITR)—a strong CYP3A inducer and inhibitor, respectively—on the pharmacokinetics (PK) of ZRN.

Methods: This was a 2-part, open-label, fixed sequence study in healthy adults. In Part A, participants (n=16) received single oral doses of ZRN 30 mg on day (D) 1 and D11 and daily oral doses of RIF 600 mg D4–10. In Part B, a second set of participants (n=16) received single oral doses of ZRN 20 mg on D1 and D9 and daily oral doses of ITR 200 mg D5–12. Blood samples were collected for 72 hours in Part A and 96 hours in Part B after each ZRN dose. ZRN PK parameters were evaluated using geometric least squares mean ratio (GMR; ZRN + RIF or ITR vs ZRN alone) and 90% confidence intervals (CI).

Results: RIF decreased exposure to ZRN; the GMR (90% CI) for Cmax and AUC∞ were 0.31 (0.27–0.37) and 0.15 (0.13–0.17), respectively. ITR increased exposure to ZRN; the GMR (90% CI) for Cmax and AUC ∞ were 1.25 (1.13–1.39) and 1.62 (1.54–1.70), respectively. Study treatments were generally well tolerated.

Conclusion: The present study confirmed CYP3A is involved in ZRN metabolism. The CYP3A inducer RIF markedly decreased ZRN exposure while the CYP3A inhibitor ITR increased exposure. The potential for altered PK should be considered if strong CYP3A inhibitors or inducers are co-administered with ZRN.