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Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications.

ABSTRACT: Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear. From our analysis, we have determined that dexamethasone-phosphate, a pro-drug widely-used clinically, has molecular and pharmacokinetic properties that make it ill-suited for use as a local therapy for hearing disorders. This polar form of dexamethasone, used as a more soluble agent in intravenous preparations, passes less readily through lipid membranes, such as those of the epithelia restricting entry at the round window membrane and stapes. Once within the inner ear, dexamethasone-phosphate is cleaved to the active form, dexamethasone, which is less polar, passes more readily through lipid membranes of the blood-perilymph barrier and is rapidly eliminated from perilymph without distributing to apical cochlear regions. Dexamethasone-phosphate therefore provides only a brief exposure of the basal regions of the cochlea to active drug. Other steroids, such as triamcinolone-acetonide, exhibit pharmacokinetic properties more appropriate to the ear and merit more detailed consideration.

SUBMITTER: Salt AN

PROVIDER: S-EPMC6133771 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications.

Salt Alec N AN Plontke Stefan K SK

Hearing research 20180311

Local drug delivery to the ear has gained wide clinical acceptance, with the choice of drug and application protocol in humans largely empirically-derived. Here, we review the pharmacokinetics underlying local therapy of the ear using the drugs commonly used in clinical practice as examples. Based on molecular properties and perilymph measurements interpreted through computer simulations we now better understand the principles underlying entry and distribution of these and other drugs in the ear ...[more]

PMID: 29551306

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Project description:Advances in protective and restorative biotherapies have created new opportunities to use site-directed, programmable drug delivery systems to treat auditory and vestibular disorders. Successful therapy development that leverages the transgenic, knock-in, and knock-out variants of mouse models of human disease requires advanced microsystems specifically designed to function with nanoliter precision and with system volumes suitable for implantation. Here we present results for a novel biocompatible, implantable, scalable, and wirelessly controlled peristaltic micropump. The micropump configuration included commercially available catheter microtubing (250 μm OD, 125 μm ID) that provided a biocompatible leak-free flow path while avoiding complicated microfluidic interconnects. Peristaltic pumping was achieved by sequentially compressing the microtubing via expansion and contraction of a thermal phase-change material located in three chambers integrated adjacent to the microtubing. Direct-write micro-scale printing technology was used to build the mechanical components of the micropump around the microtubing directly on the back of a printed circuit board assembly (PCBA). The custom PCBA was fabricated using standard commercial processes providing microprocessor control of actuation and Bluetooth wireless communication through an Android application. The results of in vitro characterization indicated that nanoliter resolution control over the desired flow rates of 10-100 nL/min was obtained by changing the actuation frequency. Applying 10× greater than physiological backpressures and ± 3 °C ambient temperature variation did not significantly affect flow rates. Three different micropumps were tested on six mice for in vivo implantation of the catheter microtubing into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. There were systematic increases in distortion product threshold shifts during the 20-min perfusions; the mean shift was 15 dB for the most basal region. A biocompatibility study was performed to evaluate material suitability for chronic subcutaneous implantation and clinical translational development. The results indicated that the micropump components successfully passed key biocompatibility tests. A micropump prototype was implanted for one month without development of inflammation or infection. Although tested here on the small murine cochlea, this low-cost design and fabrication methodology is scalable for use in larger animals and for clinical applications in children and adults by appropriate scaling of the microtubing diameter and actuator volume.

Dataset Information

Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications.

Publications

Pharmacokinetic principles in the inner ear: Influence of drug properties on intratympanic applications.

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