Authors :
Presenting Author: Joseph Hulihan, MD – Marinus Pharmaceuticals, Inc.
Maciej Gasior, MD, PhD – Marinus Pharmaceuticals, Inc.; Ian Miller, MD – Marinus Pharmaceuticals, Inc.; Heidi Whalen, BS – Marinus Pharmaceuticals, Inc.
Rationale:
Ganaxolone is a neuroactive steroid anticonvulsant approved for the treatment of seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients ≥ 2 years old and is under investigation for use in other seizure disorders. This phase one study evaluated the pharmacokinetic (PK) parameters of a second-generation ganaxolone formulation (GNX TEST) versus the current oral ganaxolone formulation (GNX REF).Methods:
In this single-center, open-label, 3-cohort, 6-period, 3 or 6-sequence crossover study, healthy adult volunteers (ages 18-55 years inclusive) were administered single ascending doses of GNX TEST ranging from 100–1200 mg vs 400–600 mg GNX REF. GNX TEST powder was administered as a sprinkle in 240 mL water under fasted or fed conditions, or with 100 g of yogurt under fed conditions, and GNX REF was administered under fed conditions, with a 4-day washout between doses. Plasma PK parameters including Tmax and ln-transformed Cmax, AUC0-t, and AUC0-inf were evaluated for all doses; 90% confidence intervals for ratios of treatment geometric means were constructed using a mixed-effects model. Safety and tolerability were assessed by physical exams, laboratory tests, and adverse event monitoring.Results:
All patients (n=18) completed the study and were included in the PK and safety datasets. GNX TEST demonstrated generally linear PK over the dose range studied. Following administration of GNX TEST under fed conditions, plasma concentrations increased with dose (Cmax of 21.4–244 ng/mL and AUC0-t of 145–2690 ng*h/mL). Exposure was significantly greater under fed versus fasted conditions at single GNX TEST doses of 100, 400, and 900 mg (fasted Cmax 4.31–25.0 ng/mL and AUC0-t 26.6–2170 ng*h/mL). Median Tmax was slightly delayed in the fed state compared to fasted. Under fed conditions, when administered with yogurt, the Tmax for GNX TEST 600 mg was two hours compared to four hours when administered with water, and Cmax increased from 115 ng/mL to 233 ng/mL. AUC0-t and AUC0-inf values did not differ when GNX TEST was administered with yogurt or water. At doses of 600, 900, and 1200 mg GNX TEST under fed conditions, the change in AUC0-t was greater than the change for Cmax with increasing dose. The most common treatment-related adverse events (TEAEs) were dizziness, headache, and somnolence. All TEAEs were mild to moderate in severity; no serious adverse events or deaths occurred.Conclusions:
GNX TEST has a predictable PK profile, demonstrating generally linear PK after single dosing over the dose range of 100-1200 mg. Exposure was significantly higher in the fed state compared to fasted. When administered with yogurt, exposure as assessed by Cmax doubled compared to administration with water; AUC0-t and AUC0-inf remained consistent whether administered with yogurt or water. Administration of 100–1200 mg doses under fasting and fed conditions with different vehicles (yogurt or water) were well-tolerated in healthy volunteers.Funding:
Marinus Pharmaceuticals, Inc.