Esther Encinas (1), Nerea Leal (1), Monica Rodriguez (1), Nieves Fernández (2), Ana Gonzalo (2), Gonzalo Hernandez (2)
(1) Drug Modeling & Consulting, Dynakin S.L., Bilbao, Spain; (2) R&D and Innovation Department, FAES FARMA S.A., Leioa (Bizkaia), Spain
Introduction: Bilastine is a non-sedating H1 antihistamine approved for treatment of allergic rhinoconjunctivitis and urticaria, at an oral dose of 20 mg once daily (OD) in adults and adolescents (≥12 years) and 10 mg OD in children <12 years. A bilastine 0.6% ophthalmic solution for allergic conjunctivitis (1 drop instilled in each eye OD) in adults and children aged ≥2 years is now under development.
Objectives: To simulate systemic PK levels arising from OD ocular administration of bilastine eye drops in children aged 2-<18 years, aimed at discarding associated safety issues. This is in accordance with the agreed paediatric investigation plan (PIP) [1], where a dedicated paediatric PK study was deemed irrelevant to the ophthalmic product performance.
Methods: Bilastine PK data in healthy adult volunteers (HVs) were obtained from 2 previous studies: study BOFT-0318-PK (n=12 HVs receiving bilastine eye drops for 5 days) and study BILA-2909/BA [2] (n=12 HVs receiving a single 10 mg iv injection of bilastine). These data were analysed in NONMEM (FOCEI method) for estimation of pre-systemic popPK parameters characterizing absorption of ophthalmic bilastine (absorption rate constant (Ka), relative bioavailability for the ocular route (F) and, if applicable, lag time) as well as associated variabilities. No covariate analysis was carried out. Goodness of fit diagnostic plots and visual predictive check (VPC) were used for model validation.
Estimated absorption kinetics of ophthalmic bilastine were assumed to be unchanged in the target paediatric population, in whom eye dimensions and pre-corneal factors are mostly like in the adult [3,4] (Scenario 1). However, two additional hypothetical (worst-case) scenarios were also explored via sensitivity analysis in the adult pre-systemic PK parameter values (Scenario 2: F increased by 30% + Ka increased by 30%; Scenario 3: F=100% + Ka increased by 30%).
In order to account for the well-known systemic PK behaviour of bilastine in the target population, systemic PK parameters (and associated variabilities) from the paediatric popPK model developed for oral bilastine were used in simulation instead of those estimated in adults above, under the assumption that systemic disposition is independent of the route of administration. The paediatric popPK model is deemed applicable in children aged ≥2 years given that all physiological processes involved in the disposition of the drug are fully mature by this age [5].
For each scenario, 500 Montecarlo datasets were simulated for ophthalmic bilastine after 28 days of ocular treatment (i.e., long-term exposure) in the paediatric population, and the 95% confidence interval of simulated individual plasma PK profiles was graphically overlapped, as a measure of safety threshold, with paediatric PK observations after repeated oral administration of bilastine 10 mg/day (study BILA-3009/PED, n=31), proven to be well tolerated in children aged ≥2 years (study BILA-3312/PED [6]).
Results: A two-compartment disposition model (same structure as for oral bilastine PK in adults and children) with a single first-order absorption rate, no lag time and proportional residual error best described pooled observations from both ocular and iv administration routes. All structural parameters were well estimated (SEE<50%). The interindividual variability (modelled as exponential) was significant for all of them except volume of central compartment. Typical values of absorption-related parameters were F=59% and Ka=0.345 h-1.
In all three simulated scenarios, the expected systemic exposure of bilastine after repeated ocular administration in children was very far below that observed in the same population after oral bilastine 10 mg/day (pre-established threshold of safety).
Conclusions: The absorption kinetics estimated for bilastine ophthalmic solution in adults were used, in conjunction with the well-known systemic PK parameters of oral bilastine in children, to simulate plasma concentrations following multiple dosing of bilastine eye drops in the target paediatric population. Plasma levels attained through the ocular route were proven to be negligible in comparison with the systemic exposure corresponding to the therapeutic paediatric oral dose (10 mg/day), thus allowing to discard safety concerns without the need to conduct paediatric PK studies.
References:
[1] EMA decision of 3 January 2019 on the agreement of a paediatric investigation plan and on the granting of a deferral and on the granting of a waiver for bilastine (Bilaxten and associated names), (EMEA-000347-PIP02-16).
[2] Sádaba B, Gómez-Guiu J, Azanza JR, Ortega I, Valiente R. Oral Availability of Bilastine. Clin Drug Investig. 2013;33(5):375–381.
[3] Coulter RA. Pediatric use of topical ophthalmic drugs. Optometry. 2004;75(7):419-29.
[4] Haeringen van NJ. Aging and the lacrimal system. Br J Ohpthalmol. 1997 Oct;81(10):824-6.
[5] Vozmediano V, Lukas JC, Encinas E, Schmidt S, Sologuren A, Valiente R, Labeaga L, Campo C, Rodriguez M. Model-informed pediatric development applied to bilastine: Analysis of the clinical PK data and confirmation of the dose selected for the target population. Eur J Pharm Sci. 2019;128:180-192.
[6] Novák Z, Yáñez A, Ildikó K, Kuna P, Tortajada-Girbés M, Valiente R. Safety and tolerability of bilastine 10 mg administered for 12 weeks in children with allergic diseases. Pediatr Allergy Immunol. 2016 Aug;27(5):493-8.
Reference: PAGE 29 (2021) Abstr 9618 [www.page-meeting.org/?abstract=9618]
Poster: Drug/Disease Modelling - Paediatrics