Francesca Del Bene (1), Silvia Maria Lavezzi (1), Matthias Grossman (2), Laura Iavarone (1)
(1) Quantitative Clinical Development Department, PAREXEL International, (2) Clinical Pharmacology Department, PAREXEL International
Objectives: A number of drugs are administered in the intratympanic space, e.g. for the treatment of sudden onset neurosensorial hearing loss, Ménière’s disease, or autoimmune ear diseases [1,2]. Intratympanic (IT) drug delivery refers to drug administration in the middle ear beyond the tympanum with these main objectives: maximize the delivery in the site of interest; minimize systemic exposure and side effects [2,3,4]. After systemic administration, drug distribution to the inner ear would be limited by the blood–labyrinth barrier (BLB), physiologically similar to the blood–brain barrier [3,5], leading to low bioavailability (~<5%) [1]. IT administration enables the drug to bypass the BLB and access directly the inner ear: the drug diffuses from the middle ear across the round window membrane (RWM), located at the end of the scale tympani (separating the middle from the inner ear and protecting the inner ear) [6,7]. Factors such as the permeability of RWM to drugs, diffusion and clearance mechanisms affect perilymph drug levels responsible for efficacy. Animal studies show high variability in perilymph drug levels after RWM applications [1]. Evaluation of pharmacokinetics (PK) after IT administration is challenging due to difficulty in accessing the inner ear and its limited size [8,9]. Therefore, the development of a model to predict inner ear and systemic PK following local administration would support dosing regimen selection and study design in both preclinical and clinical settings: the objective of the present work was to review modelling approaches proposed in the literature.
Methods: A literature search was performed in PubMed and Google Scholar (keywords: intratympanic pharmacokinetic; intratympanic model; intratympanic administration; inner ear administration). Additional articles were selected among the references of those initially found. Exclusion criteria were: (i) no full text available; (ii) focus on administration routes other than IT; (iii) no relevant information on PK after IT administration and no modelling approach described. Current capabilities of the main tools for physiological based (PB) PK modelling (GastroPlus, PKSim, and Symcip [10,11,12]) were investigated.
Results: A total of 39 papers were found; 10 were discarded because of (i), 8 because of (ii), 7 because of (iii). No examples of empirical compartmental models for IT administration were found, neither in preclinical nor clinical setting. PB models of the guinea pig, mouse, and human ear were developed and implemented in the computer simulation software FluidSim by Washington University [13,14]. This tool simulates solute movements in fluid and tissue spaces of the cochlea and vestibular systems; elimination to systemic circulation is considered [8,13,15,16,17]. In the preclinical setting, the FluidSim model has been applied to explore perilymph PK both after systemic and local administration [15,16,17,18]. In Ménière’s disease and idiopathic sudden sensorineural hearing loss patients, inner ear drug concentrations after IT administration were computed and associated with hearing changes, and risk of hearing loss and deafness [19,20]. Furthermore, in [21] mathematical equations to quantify the permeability coefficient through the RWM based on drugs’ physicochemical properties were obtained. State-of-the-art PBPK tools such as GastroPlus, PKSim, and Symcip do not include a description of the ear and do not allow simulation of IT administration.
Conclusions: Literature search results highlighted a knowledge gap about PK after IT administration. The physiological structure of the ear is complex and extrapolation from animal to humans is not easy: animals like guinea pigs are used in preclinical studies, however anatomical differences with humans should be considered. Furthermore, data collection in the inner ear is challenging both in animals and (especially) in humans [8,9], because of its invasiveness and of possible cerebrospinal fluid contamination. Empirical approaches have not been attempted yet, however simple compartmental PK models and deconvolution techniques (to separate the intratympanic component of systemic absorption) might be coupled to describe drugs’ PK after IT administration and scale across species. A PB model of the ear for different species is currently available, however well-defined criteria for parameters selection and integration of a whole-body description for systemic exposure prediction are still open challenges.
References:
[1] Salt, A. N., & Plontke, S. K. (2009). Principles of local drug delivery to the inner ear. Audiology and Neurotology, 14(6), 350-360.
[2] Chirteş, F., & Albu, S. (2013). An overview of pharmacology and clinical aspects concerning the therapy of cochleo-vestibular syndromes by intratympanic drug delivery. Clujul Medical, 86(3), 185.
[3] McCall AA, Swan EE, Borenstein JT, et al. (2010). Drug delivery for treatment of inner ear disease: current state of knowledge. Ear Hear 31:156–65.
[4] Duan ML, Chen ZQ. (2009). Permeability of round window membrane and its role for drug delivery: our own findings and literature review. J Otol 4:34–43.
[5] Liu HZ, Hao JS, Li KS. (2013). Current strategies for drug delivery to the inner ear. Acta Pharm Sin B 3:86–96.
[6] Juhn SK, Hamaguchi Y, Goycoolea M. (1989). Review of round window membrane permeability. Acta Otolaryngol Suppl 457:43–8.
[7] Goycoolea MV, Lundman L. (1997). Round window membrane. Structure function and permeability: a review. Microsc Res Tech 36: 201–11.
[8] Plontke SK, Salt AN. (2003). Quantitative interpretation of corticosteroid pharmacokinetics in inner fluids using computer simulations. Hear Res 182:34–42.
[9] Plontke SK, Salt AN. (2006). Simulation of application strategies for local drug delivery to the inner ear. ORL J Otorhinolaryngol Relat Spec 68:386–92.
[10] https://www.simulations-plus.com/software/gastroplus/
[11] http://www.open-systems-pharmacology.org/
[12] https://www.certara.com/software/physiologically-based-pharmacokinetic-modeling-and-simulation/simcyp-simulator/?ap%5B0%5D=PKPD&ap%5B1%5D=PBPK
[13] Plontke, S. K., Siedow, N., Wegener, R., Zenner, H. P., & Salt, A. N. (2007). Cochlear pharmacokinetics with local inner ear drug delivery using a three-dimensional finite-element computer model. Audiology and Neurotology, 12(1), 37-48.
[14] https://oto.wustl.edu/saltlab/Cochlear-Fluids-Simulator
[15] Salt, A. N., Hartsock, J. J., Gill, R. M., Piu, F., & Plontke, S. K. (2012). Perilymph pharmacokinetics of markers and dexamethasone applied and sampled at the lateral semi-circular canal. Journal of the Association for Research in Otolaryngology, 13(6), 771-783.
[16] Hahn, H., Salt, A. N., Schumacher, U., & Plontke, S. K. (2013). Gentamicin concentration gradients in scala tympani perilymph following systemic applications. Audiology and Neurotology, 18(6), 383-391.
[17] Salt, A. N., Hartsock, J. J., Gill, R. M., King, E., Kraus, F. B., & Plontke, S. K. (2016). Perilymph pharmacokinetics of locally-applied gentamicin in the guinea pig. Hearing research, 342, 101-111.
[18] Plontke, S. K., Wood, A. W., & Salt, A. N. (2002). Analysis of gentamicin kinetics in fluids of the inner ear with round window administration. Otology & neurotology, 23(6), 967-974.
[19] Salt, A. N., Gill, R. M., & Plontke, S. K. (2008). Dependence of hearing changes on the dose of intratympanically applied gentamicin: a meta‐analysis using mathematical simulations of clinical drug delivery protocols. The Laryngoscope, 118(10), 1793-1800.
[20] Liebau, A., Pogorzelski, O., Salt, A. N., & Plontke, S. K. (2017). Hearing changes after intratympanically applied steroids for primary therapy of sudden hearing loss: a meta-analysis using mathematical simulations of drug delivery protocols. Otology & neurotology: official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 38(1), 19.
[21] Zhang Y, Su H, Wen L, Yang F, Chen G. (2016) Mathematical modeling for local trans-round window membrane drug transport in the inner ear, Drug Delivery, 23:8, 3082-3087, DOI: 10.3109/10717544.2016.1149745
Reference: PAGE 28 (2019) Abstr 8867 [www.page-meeting.org/?abstract=8867]
Poster: Drug/Disease Modelling - Other Topics