Plasma Concentration as a Proxy for Perilymph Drug Levels: Preclinical and Clinical Dexamethasone Measures with a Long-Acting Formulation for Precise Delivery to the Round Window Membrane.

Objective: To use animal pharmacokinetic data and FluidSIM modeling to estimate human dexamethasone perilymph concentrations from plasma concentration measurements over time following a single intratympanic administration of SPT-2101.

Study design: Perilymph and plasma dexamethasone concentrations were measured in guinea pigs and African green monkeys over 3 to 6 weeks post-intratympanic administration of SPT-2101. Plasma concentrations of dexamethasone were measured in Ménière's disease patients post-intratympanic administration of SPT-2101. FluidSIM was trained on the correlations of animal plasma and animal perilymph levels, allowing the human perilymph drug time course for SPT-2101 to be predicted from measured human plasma dexamethasone concentrations.

Setting: Tertiary care neurotology clinic in Perth, Australia.

Patients: Nine adults with unilateral definite Ménière's disease per Barany Society criteria.

Intervention: Intratympanic SPT-2101, a single injection of a long-acting gel formulation of dexamethasone precisely delivered at the round window.

Main outcome measure: Estimated dexamethasone levels in human perilymph following a single administration of SPT-2101 at the round window over time.

Results: Perilymph dexamethasone concentrations were above estimated therapeutic levels for up to 35 days in guinea pigs and at least 21 days in African green monkeys. In human subjects, plasma dexamethasone concentrations were detected for 2 weeks post-administration. Animal middle ear, plasma and perilymph drug interrelationships were compared to FluidSIM simulations, providing rationale for correlating dexamethasone concentrations in the respective compartments. Comparable simulations of human plasma concentrations predicted perilymph dexamethasone therapeutic levels in humans for 23-55 days.

Conclusions: Sustained release dexamethasone from SPT-2101 precisely delivered at the round window provides prolonged and durable estimated perilymph concentrations in clinical subjects.