Sage Therapeutics, Inc. Cambridge, Massachusetts, United States
Background: Zuranolone (ZRN) is a positive allosteric modulator of synaptic and extrasynaptic GABAa receptors and a neuroactive steroid in clinical development as an oral, once-daily, 14-day treatment course for adults with major depressive disorder and postpartum depression. The potential of ZRN to precipitate a drug-drug interaction (DDI) due to modulation of CYP P450 enzyme activity was evaluated using in vitro and in vivo methods. Methods: In vitro methods included human liver microsome and hepatocyte incubations. Based on in vitro findings, the induction potential of ZRN on CYP3A4 and 2B6 pathways was further assessed in healthy adults. In the clinical (in vivo) study, participants (n=12) received once-daily ZRN 30 mg on Day (D) 3–9; bupropion (BUP) 100 mg on D1 and D11; and simvastatin (SIM) 20 mg on D2 and D10. Plasma samples were collected before and after ZRN dosing. BUP and SIM pharmacokinetic (PK) parameters were evaluated using geometric least squares mean ratio (GMR; post- vs pre-ZRN dosing) and corresponding 90% confidence intervals (CIs). Results: Calculated R1 values for direct CYP inhibition were below the critical value of 1.02. There was no evidence of time- or metabolism-dependent inhibition. ZRN demonstrated induction of CYP3A4 2B6 based on mRNA expression and/or catalytic activity. In the clinical study, SIM PK parameters increased slightly post- vs pre-ZRN dosing: Cmax, GMR (90% CI) 1.10 (0.85–1.43); AUC0–∞, 1.13 (1.04–1.23). BUP Cmax decreased slightly post- vs pre- ZRN dosing (0.92 [0.77–1.11]) while AUC0–∞ was unchanged (1.04 [0.96–1.14]). Conclusion: Based on in vitro and clinical data, the likelihood for ZRN to precipitate DDIs due to CYP inhibition or induction is low.
.jpg "Joi Dunbar, PharmD (she/her/hers) photo")