Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design

Vozmediano, Valvanera; Sologuren, Ander; Lukas, John C.; Leal, Nerea; Rodríguez, M.

doi:10.1007/s11095-017-2248-6

Cited by 14 publications

(17 citation statements)

References 38 publications

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“…Results from the post hoc PK study of bilastine in children aged 6-11 years with allergic rhinoconjunctivitis or urticaria align with those from a larger pediatric population (aged 2-11 years) which indicated a lack of age dependence for bilastine PK [11,12]. The current PK analysis was limited to children aged 6-11 years, which is in line with the approved pediatric indication for bilastine in Europe: ≥ 6 years of age with a body weight of ≥ 20 kg.…”

Section: Discussionmentioning

confidence: 53%

“…Previous PK population modeling of children used subjects aged 4-11 years [11,12]. This post hoc analysis focuses on children aged 6-11 years (n = 24), in line with the approved pediatric indication in Europe.…”

Section: Pharmacokinetic Datamentioning

confidence: 99%

“…Pharmacokinetic (PK)/pharmacodynamic (PD) modeling in healthy adult subjects, complemented with noncompartmental analysis, demonstrated linear kinetics of orally administered bilastine over a dose range of 2.5 to 220 mg [10]. In children aged 2 to 11 years, an ontogenic model based on adult data and PK/PD simulations supported the selection of a bilastine dose of 10 mg/day [11], which was confirmed in a clinical PK study of children aged 4 to 11 years with allergic rhinoconjunctivitis or urticaria [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria

Rodríguez¹,

Vozmediano²,

García-Bea

et al. 2020

Eur J Pediatr

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Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults and children aged ≥ 6 years. Pharmacokinetic data for children aged 6-11 years were extracted post hoc from a study in which children (2-11 years) with allergic rhinoconjunctivitis or urticaria received oral bilastine (10 mg/day). Maximum plasma concentration (C max) and area under the plasma concentration curve (AUC) data were compared with adult pharmacokinetic data from seven clinical studies (bilastine 20 mg/day). Safety data for children aged 6-11 years were extracted post hoc from a phase III randomized controlled trial of children (2-11 years) with allergic rhinoconjunctivitis or chronic urticaria receiving once-daily bilastine 10 mg or placebo for 12 weeks. Exposure and C max values were similar for children (6-11 years) and adults: median pediatric/adult ratios for AUC 0-24 and C max were 0.93 and 0.91, respectively. There was no significant difference in the incidence of treatment-emergent adverse in children (6-11 years) receiving bilastine 10 mg or placebo. Conclusion: Pharmacokinetic and safety analyses in children aged 6-11 years support the suitability of the pediatric dose of bilastine 10 mg and confirm that the safety profiles of bilastine and placebo are similar. What is Known: • Bilastine, a second-generation antihistamine, is approved in Europe for the treatment of allergic rhinoconjunctivitis and urticaria in adults (20 mg/day) and children aged ≥ 6 years (10 mg/day). • An ontogenic model based on adult data and pharmacokinetic/pharmacodynamic simulations supported the selection of a bilastine dose of 10 mg/day in children aged 2-11 years. Bilastine 10 mg/day was shown to have a safety profile similar to that of placebo in a large phase III randomized clinical trial in children aged 2-11 years. What is New: • As bilastine is approved in Europe for children aged ≥6 years, the current study reports the results of two post hoc analyses of pharmacokinetic and safety data in children aged 6-11 years. • Analysis of pharmacokinetic and safety data in children aged 6-11 years supports the suitability of the pediatric dose of bilastine 10 mg and confirms that its safety profile is similar to that of placebo.

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Section: Discussionmentioning

confidence: 53%

Section: Pharmacokinetic Datamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria

Rodríguez¹,

Vozmediano²,

García-Bea

et al. 2020

Eur J Pediatr

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“…More recently, bilastine was approved widely for use in children aged 6-11 years (who weigh 20 kg) 85,86 . This approval was based on data from studies included in the bilastine Paediatric Investigation Plan, approved by the EMA Paediatric Committee, which included a paediatric pharmacokinetic study 87,88 and an international, double-blind, randomized, placebo-controlled study evaluating safety and tolerability 89 , both performed in children aged >2 years to <12 years.…”

Section: School-age Childrenmentioning

confidence: 99%

“…A model-informed development approach was used to select the paediatric dose and design the sampling schedule for the pharmacokinetic study 87,88 . The multicentre, adaptive, open-label, repeated-administration pharmacokinetic study enrolled children in two age groups, 6 to <12 years (n ¼ 24) and 2 to <6 years (n ¼ 7).…”

Section: School-age Childrenmentioning

confidence: 99%

Bilastine: a lifetime companion for the treatment of allergies

Church

Tiongco-Recto

Ridolo

et al. 2019

Current Medical Research and Opinion

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Objective: Bilastine is a potent and highly selective H 1 -antihistamine approved for the treatment of allergic rhinoconjunctivitis and urticaria. This article summarizes available data on the use of bilastine in the treatment of allergic disorders in different age groups, including younger and older adults, and school-age children and adolescents. Methods: A PubMed literature search ("bilastine") was conducted on 25 February 2019. Additional literature known to the authors and identified from the reference lists of cited publications was included. Results: Bilastine is administered orally at a dose of 20 mg once daily in adults and adolescents aged 12 years and 10 mg once daily in children aged 6 to <12 years. Clinical trials have demonstrated its efficacy at improving nasal and ocular symptoms in patients with allergic rhinitis, and wheals and itching in patients with urticaria. It has a rapid onset of action and long duration of action. Bilastine does not undergo significant metabolism and does not interact with the CYP450 system, which limits its potential for drug-drug interactions. No dosage adjustments are required in patients with renal or hepatic impairment, or in the elderly. Bilastine is generally well tolerated, even when administered at above-standard doses. It does not exhibit anticholinergic effects or cardiotoxic effects, shows no central nervous system penetration and has minimal sedative properties. It has been shown to improve health-related quality of life. Conclusions: Bilastine is a suitable option for the treatment of patients with allergic rhinoconjunctivitis or urticaria across age groups from school-age children to elderly patients.

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Application of a dual mechanistic approach to support bilastine dose selection for older adults

Kim

Rodríguez³

et al. 2021

CPT Pharmacom & Syst Pharma

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The objective of this study was to evaluate bilastine dosing recommendations in older adults and overcome the limitation of insufficient data from phase I studies in this underrepresented population. This was achieved by integrating bilastine physicochemical, in vitro and in vivo data in young adults and the effect of aging in the pharmacology by means of two alternative approaches: a physiologically-based pharmacokinetic (PBPK) model and a semi-mechanistic population pharmacokinetic (Senescence) model. Intestinal apical efflux and basolateral influx transporters were needed in the PBPK model to capture the observations from young adults after single IV (10mg) and PO (20 mg) doses, supporting the hypothesis of involvement of gut transporters on secretion. The model was then used to extrapolate the PK to elderly subjects considering their specific physiology. Additionally, the Senescence model was develop starting from a published PopPK model, previously applied for pediatrics, and incorporating declining functions on different physiological systems and changes in body composition with aging. Both models were qualified using observed data in a small group of young elderlies (N=16, mean age=68.69 years). The PBPK model was further used to evaluate the dose in older subjects (mean age=80 years) via simulation. The PBPK model supported the hypothesis that basolateral influx and apical efflux transporters are involved in bilastine PK. Both, PBPK and Senescence models indicated that 20 mg QD dose is safe and effective for geriatrics of any age. This approach provides an alternative to generate supplementary data to inform dosing recommendations in underrepresented groups in clinical trials.

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Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design

Abstract: The model successfully predicted bilastine PK in pediatrics and optimally assisted the selection of the dose and sampling scheme for the trial in children. The selected dose was considered suitable for younger children and the forthcoming safety study in children aged 2 to <12 years.

Cited by 14 publications

References 38 publications

Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria

Pharmacokinetics and safety of bilastine in children aged 6 to 11 years with allergic rhinoconjunctivitis or chronic urticaria

Bilastine: a lifetime companion for the treatment of allergies

Application of a dual mechanistic approach to support bilastine dose selection for older adults

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