Recent mouse knockout studies identified
adapter protein-2 associated
kinase 1 (AAK1) as a viable target for treating neuropathic pain.
Potent small-molecule inhibitors of AAK1 have been identified and
show efficacy in various rodent pain models. (S)-1-((2′,6-Bis(difluoromethyl)-[2,4′-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine
(BMS-986176/LX-9211) (34) was identified as a highly
selective, CNS penetrant, potent AAK1 inhibitor from a novel class
of bi(hetero)aryl ethers. BMS-986176/LX9211 (34) showed
excellent efficacy in two rodent neuropathic pain models and excellent
central nervous system (CNS) penetration and target engagement at
the spinal cord with an average brain to plasma ratio of 20 in rat.
The compound exhibited favorable physicochemical and pharmacokinetic
properties, had an acceptable preclinical toxicity profile, and was
chosen for clinical trials. BMS-986176/LX9211 (34) completed
phase I trials with good human pharmacokinetics and minimum adverse
events and is currently in phase II clinical trials for diabetic peripheral
neuropathic pain (ClinicalTrials.gov identifier: NCT04455633) and
postherpetic neuralgia (ClinicalTrials.gov identifier: NCT04662281).
Self-emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water-soluble drugs to improve exposure in high-dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs. SEDDS formulations of two lipophilic salts-atazanavir-2-naphthalene sulfonic acid (ATV-2-NSA) and atazanavir-dioctyl sulfosuccinic acid (ATV-Doc)-were characterized and their performance compared to atazanavir (ATV) free base formulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro, in vivo, and in silico methods. ATV-2-NSA exhibited ∼6-fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12mg/mL. In rat PK studies at 60mg/kg, the ATV-2-NSA SEDDS emulsion had comparable exposure to the free-base solution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose-dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilic salts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.
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