Zuranolone

Zuranolone is a synthetic neuroactive steroid (NAS) that exhibits potent positive allosteric modulation of the gamma-aminobutyric acid-A (GABA_A) receptor. Zuranolone enhances GABAergic activity at synaptic and extrasynaptic GABA_A receptors and has also been shown to increase cell surface expression of GABAA receptors in in vitro studies. Zuranolone may exert antidepressant effects by enhancing GABAergic inhibition.

Cardiac electrophysiology

At a dose up to 2 times the MRHD, zuranolone does not cause clinically significant QTc interval prolongation nor any other clinically significant effect on other electrocardiography (ECG) parameters.

Absorption

Once-daily administration of zuranolone 50 mg resulted in accumulation of approximately 1.5-fold in systemic exposures and steady state was achieved in 3 to 5 days.

Following oral administration, peak zuranolone concentrations occur at 5 to 6 hours post-dose.

Effect of food

Following administration of zuranolone 30 mg to healthy volunteers, the maximum serum concentration (C_max) increased 228% and the AUC increased 55% with a low-fat meal (400 to 500 calories, 25% fat) compared to fasted conditions. The C_max increased 334% and the AUC increased 90% with a high-fat meal (800 to 1000 calories, 50% fat) compared to fasted conditions. The time at maximum concentration (t_max) was not impacted by food. Exposure at doses up to 90 mg remained approximately dose linear with consumption of a moderate-fat meal (700 calories; 30% fat).

Distribution

The volume of distribution of zuranolone following oral administration is high (>500 L) and was independent of dose. Zuranolone did not distribute preferentially into red blood cells.

Zuranolone is highly protein bound (>99.5%) to plasma proteins.

Distribution into breast milk

The distribution of zuranolone into human breast milk was studied in a group of 14 healthy lactating women treated with daily oral administration of zuranolone 30 mg for 5 days. At steady state (Day 5), the calculated daily infant dose was low (approximately 0.00135 mg/kg/day), reflecting a mean RID of 0.357% compared to the maternal dose. From a simulation, the expected mean RID associated with a 50 mg maternal dose was 0.738% for an infant with a milk intake of 150 mL/kg/day and 0.984% for an infant with a milk intake of 200 mL/kg/day.

Biotransformation

Zuranolone undergoes extensive metabolism, with CYP3A identified as a primary enzyme involved. There were no human metabolites circulating at >10% of total drug-related material and none are considered to contribute to the therapeutic effects of zuranolone.

Zuranolone is not an inhibitor of CYP1A2, CYP2B6 or CYP2C19 and is not expected to be an inhibitor of CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 at clinically relevant concentrations.

Zuranolone is not expected to be an inhibitor of BSEP, BCRP, MDR1, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1, or OCT2 at clinically relevant concentrations. Zuranolone is not a substrate of P-glycoprotein.

Clinical DDI studies indicate that repeated administration of zuranolone prior to administration of simvastatin (CYP3A substrate) or bupropion (CYP2B6 substrate) did not alter the exposure of simvastatin or bupropion. Zuranolone is not expected to cause a drug interaction through CYP450 enzyme induction.

Elimination

The terminal half-life of zuranolone (t_1/2) is approximately 19.7 to 24.6 hours in an adult population. The clearance of zuranolone was independent of dose. The mean apparent clearance (CL/F) of zuranolone is 32.7 L/h.

Excretion

Following oral administration of radiolabelled zuranolone, 45% of the dose was recovered in urine as metabolites with negligible unchanged zuranolone and 41% in faeces as metabolites with less than 2% as unchanged zuranolone.

Pharmacokinetics in special patient groups

Weight, race, or age

The pharmacokinetics (PK) of zuranolone was similar between healthy subjects and subjects with PPD.

Black or African American subjects had a 14% higher CL/F compared to subjects of other races (Asian, White, or other) but this increase was not clinically meaningful.

No dose adjustments are necessary based on weight, race, or age.

Renal impairment

Exposure to zuranolone was increased in patients with moderate (eGFR 30 to 59 mL/min) and severe (eGFR 15 to 29 mL/min) renal impairment. Zuranolone has not been studied in patients with eGFR of <15 mL/min requiring dialysis.

Hepatic impairment

C_max and AUC_inf for zuranolone were unchanged in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment compared to matched healthy subjects. C_max was 24% lower and AUC_inf was 56% higher in patients with severe (Child-Pugh class C) hepatic impairment.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Reproductive toxicity

In the pivotal rat embryo-foetal development study, a low incidence of foetal malformations was noted from the mid-dose and higher. The developmental no adverse effect level (NOAEL) was 2.5 mg/kg/day. Exposures at this dose are approximately 3-fold above the expected exposures in humans. In mice, an increase in cleft palate was noted from the mid-dose and higher, which could be related to lower foetal body weight. The exposure margin at the NOAEL was 1.9-fold above the expected exposures in humans. In rabbits no malformations were seen, however, all doses tested resulted in exposures below those expected in humans.

In a pre‑/postnatal development study in rats, total litter loss and increased pup mortality due to lack of nursing occurred at the mid-dose and higher. The NOAEL for pre and postnatal development was the low dose, resulting in a 2-fold exposure margin as compared to expected human exposure.

At zuranolone exposures 5.6-fold greater than MRHD, a relative elevation in neuronal death was observed in rats exposed to a single dose of zuranolone on postnatal Day 7, which corresponds in humans to a period of brain development beginning during the third trimester of pregnancy and continuing up to a few years after birth.

Toxicity in juvenile animals

In juvenile toxicity studies in rats, zuranolone treatment-related findings were consistent with those noted in adult animals.