Valvanera Vozmediano (1,2), Esther Encinas (1), Monica Rodriguez (1), John C. Lukas (1), Nerea Leal (1), Maria Panselina (1,3), Román Valiente (4)
(1) Drug Modeling & Consulting, Dynakin S.L., Bilbao, Spain; (2) Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida; (3) Department of Pharmacology. University of the Basque Country. Spain; (4) Clinical Research Department, FAES FARMA S.A., Leioa (Bizkaia), Spain.
Objectives: Bilastine is a non-sedating H1 receptor antagonist approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD) [1]. Optimal attributes can be anticipated for its clinical use in paediatrics due to its favourable safety and tolerability [2] and age-independent PD profile [3]. The aim of this work was to characterize bilastine PK in children through population modelling of data from clinical trial BILA-3009/PED (“Multicenter, International, Adaptive, Open-label, Repeated Administration PK Study of bilastine (10 mg/day) in Children from 2 to <12 years with AR or U”) as part of bilastine paediatric drug development. The primary objective was to ascertain whether the proposed dose in the above paediatric subset (10 mg/day) matches systemic exposure seen in adults at the 20 mg/day dose.
Methods: BILA-3009/PED was an adaptive limited sampling confirmatory study, optimized by means of an ontogenic predictive PK/PD model developed in children between 2 and 12 years based on prior knowledge [3]. The paediatric PK clinical dataset comprised a total of 31 patients from 4 to <12 years treated with 10 mg oral bilastine daily (sparse PK sampling performed up to 24 h following administration of the 6th dose). PopPK models were developed in NONMEM, FOCE method. One and two compartment disposition models with first-order absorption and possible contribution of a lag time were explored. The influence of covariates (e.g. age, body weight, height, sex and creatinine clearance) was then evaluated by a stepwise procedure. Final model establishment and validation was done using standard statistical and diagnostic criteria for parametric non-linear mixed effects models, including goodness of fit plots, visual predictive check (VPC) and posterior predictive check (PPC). Suitability of the final paediatric dataset to fulfill the trial stopping criteria (i.e., model completeness and non-dependence of exposure on decreasing age) was also evaluated. In a final step, the popPK model along with observations and additional analyses were used to assess the suitability of the selected paediatric dose (10 mg/day) through comparison of PK metrics in children with those in adults (20 mg/day).
Results: A two-compartment disposition model (same structure as for bilastine PK in adults [4]) with a lag time and proportional residual error provided the best description of the paediatric observations. Parameter estimates were: Ka, 1.29 h-1; CL/F, 12.5 L/h; Vc/F, 19.7 L; Vp/F, 17.4 L; Q/F, 2.01 L/h; Tlag, 0.183 h. The interindividual variability (modelled as exponential) was well defined and significant for Ka and CL/F. None of the studied covariates was significantly predictive for inclusion. Final popPK model was positively qualified and its predictive capacity was confirmed at all ages recruited hence supporting that the entire group of children [4 to <12 years] belongs to the same PK population (stopping rules pre-stablished to finalize the trial were thus fulfilled). Children from 2 years were deemed to belong to the same population as well, given that the physiology concerned is already mature by this age, as further supported by a number of additional analyses (including confirmation of ontogenic assumptions and physiological interpretation of bilastine PK processes) [3]. No significant difference was observed in AUC and Cmax between paediatric age groups, all of which were well within the range observed in adults after the therapeutic dose (20 mg daily). Min-Max range for AUC0-24h was 958-2110, 532-1653 and 481-2528 ng·h/mL in children <6 years, children ≥6 years and adults, respectively; corresponding values for Cmax were 118-347, 129-447 and 83-924 ng/mL. The above approach supports the choice of 10 mg OD p.o. for the entire children subset, as further confirmed in a placebo-controlled safety trial including 509 children from 2 to <12 years (BILA-3312/PED) [5].
Conclusions: A popPK model characterizing bilastine PK behaviour in children aged from 4 to <12 years was successfully developed and positively qualified from observations in a limited sampling confirmatory study in paediatrics. The achievement of comparable (i.e., within the range) drug exposure to that observed in adults after the therapeutic dose of 20 mg, together with the additional integrative analysis, served to confirm the validity of the 10 mg daily dose for the target paediatric subset (2 to <12 years).
References:
[1] Bachert C, Kuna P, Zuberbier T. Bilastine in allergic rhinoconjunctivitis and urticaria. Allergy. 2010;65:1–13.
[2] Sadaba B, Azanza JR, Gomez-Guiu A, Rodil R. Critical appraisal of bilastine for the treatment of allergic rhinoconjunctivitis and urticaria. Ther. Clin. Risk Manag. 2013;9:197–205.
[3] Vozmediano V, Sologuren A, Lukas JC, Leal N, Rodriguez M. Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design. Pharm Res. 2017 Dec;34(12):2720-2734.
[4] Jauregizar N, de la Fuente L, Lucero ML, Sologuren A, Leal N, Rodríguez M. Pharmacokinetic-pharmacodynamic modelling of the antihistaminic (H1) effect of bilastine. Clin. Pharmacokinet. 2009;48:543–54.
[5] 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 27 (2018) Abstr 8665 [www.page-meeting.org/?abstract=8665]
Poster: Drug/Disease Modelling - Paediatrics