Authors :
Presenting Author: Joshua Weavil, PhD – Lipocine Inc.
Jonathan Ogle, PhD – Lipocine Inc.
Min-Jee Goh, PharmD, PhD – Lipocine Inc.
Joel Frank, BS – Lipocine Inc.
Samuel Akapo, PhD – Lipocine Inc.
Benjamin Bruno, PharmD, PhD – Lipocine Inc.
Nachiappan Chidambaram, PhD – Lipocine Inc.
Anthony DelConte, MD – Lipocine Inc.
Mahesh Patel, PhD – Lipocine Inc.
Rationale:
As many as 900,000 women of childbearing age have active epilepsy and face difficult choices. Many available therapies present structural and neurodevelopmental teratogenic risks. Safe and effective treatment of WWE can be challenging and require therapy adjustment and monitoring due to pharmacokinetic and pharmacodynamic changes during pregnancy. There is an unmet need for an oral ASM that is safe for women of childbearing age, including during pregnancy and postpartum periods.
Oral formulations comprising a bioidentical NAS metabolite of progesterone, eltanolone, referred to as LPCN 2101, is a positive allosteric modulator (PAM) of GABAAR being developed to treat seizure disorders. Eltanolone is a unique GABAAR modulator expected to act on both synaptic and extrasynaptic receptors. The anti-seizure potential of eltanolone has been established in numerous preclinical studies. However, due to its poor aqueous solubility, there are significant challenges for effective oral bioavailability of eltanolone. The objective of this study was to enable effective oral delivery of eltanolone and assess its toxicokinetics via preclinical evaluation.
Methods:
Sixteen female dogs were randomized to receive low, medium, or high doses of LPCN 2101 or vehicle administered by oral capsule daily for 14 days. Plasma eltanolone levels and PK were measured by LC/MS. Ophthalmic and electrocardiographic exams and blood and urine sample collection occurred pre- and post-dose. Clinical observations were made throughout the study. All animals were necropsied on day 15 and tissues were analyzed by histopathology.
Results:
Effective oral delivery of LPCN 2101 was achieved, and exposure increased with dose. Day 1 Cmax ranged from ~70 to ~460 ng/mL with AUC from 99 to 398 ng*h/mL. All animals survived to the scheduled necropsy on day 15. There was one case of granuloma in skeletal muscle with the highest tested dose and microscopic histologic findings with LPCN 2101, but these events were considered spontaneous and not related to drug. There were no drug-related adverse findings with respect to clinical observation, ophthalmic exam, electrocardiography, clinical laboratory tests, urinalysis, necropsy, organ weight changes, and histopathology.
Conclusions:
Oral enablement of LPCN 2101, a unique bioidentical NAS with good tolerability, supports clinical testing of LPCN 2101 as a potential oral therapy option for seizure disorders. Noting observed lower NAS concentrations during the third trimester of pregnancy were associated with increased seizure burden, oral LPCN 2101 may be particularly relevant for women with epilepsy of childbearing age as an ASM with favorable benefit to risk profile.
Funding: Lipocine Inc.