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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

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Abstract

Purpose

Bilastine is an H1 antagonist whose pharmacokinetics (PK) and pharmacodynamics (PD) have been resolved in adults with a therapeutic oral dose of 20 mg/day. Bilastine has favorable characteristics for use in pediatrics but the PK/PD and the optimal dose in children had yet to be clinically explored. The purpose is to: (1) Develop an ontogenic predictive model of bilastine PK linked to the PD in adults by integrating current knowledge; (2) Use the model to design a PK study in children; (3) Confirm the selected dose and the study design through the evaluation of model predictability in the first recruited children; (4) Consider for inclusion the group of younger children (< 6 years).

Methods

A semi-mechanistic approach was applied to predict bilastine PK in children assuming the same PD as described in adults. The model was used to simulate the time evolution of plasma levels and wheal and flare effects after several doses and design an adaptive PK trial in children that was then confirmed using data from the first recruits by comparing observations with model predictions.

Results

PK/PD simulations supported the selection of 10 mg/day in 2 to <12 year olds. Results from the first interim analysis confirmed the model predictions and design hence trial continuation.

Conclusion

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.

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Abbreviations

%:

Percentage

ADME:

Absorption distribution metabolism excretion

AEs:

Adverse Events

AR:

Allergic Rhinoconjuctivitis

AUC:

Area under the curve

CI:

Confidence interval

CL:

Clearance

CLr:

Renal clearance

CLu:

Unbound clearance

Cmax:

Maximum plasma concentration

CO:

Cardiac output

CYP450:

Cytochrome P450

EMA:

European medicine agency

F:

Bioavailability

FDA:

Food and drug administration

fu:

Unbound plasma fraction

g/mol:

Grams per mol

GFR:

Glomerular filtration rate

h:

Hour

IC50:

Half maximal inhibitory concentration

ICH:

International conference on harmonization

Ka:

Absorption rate constant

L:

Liter

L/h:

Liter per hour

Log P:

Computational logarithm of the partition coefficient between n-octanol and water

M:

Albumin molar concentration

M&S:

Modeling & simulation

mg:

Milligram

mg/day:

Milligram per day

mg/ml:

Milligram per milliliter

MIDD:

Model informed drug development

ng.h/ml:

Nanogram. hour/ml

ng/ml:

Nanogram per milliliter

OATP:

Organic anion transporting peptide

PD:

Pharmacodynamics

PDCO:

Pediatric committee of the EMA

P-gp:

P-glycoprotein

PIP:

Pediatric investigation plan

PK:

Pharmacokinetics

pka:

Negative base-10 logarithm of the acid dissociation constant

Q:

Distribution or intercompartmental clearance

QD:

Once a day (from the Latin quaque die)

SEE:

Standard error of estimates

TBW:

Total body water

U:

Urticaria

Vc:

Central volume of distribution

Vp:

Peripheral volume of distribution

VPC:

Visual predictive check

Vss:

Steady state volume of distribution

WT:

Body weight

yr:

Year

yrs:

Years

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Acknowledgments and Disclosures

One of the authors (VV) became involved thanks to support from the Department of Industry, Commerce and Tourism of the Basque Government (Ikertu). This work is also part of the doctoral thesis of the corresponding author (directed by Dr. Rosario Calvo). Finally, the authors of this manuscript would also like to thank Maria Luisa Lucero for her contribution during the management of FAES FARMA, S.A. Research Department, as well as Roman Valiente for his contribution as Director of the Clinical Research Department of FAES FARMA, S.A. Dr. Ander Sologuren is employee of FAES FARMA, S.A., Spain. None of the other authors have any conflicts of interest other than receiving funding from FAES FARMA, S.A., for designing the trial and conducting the modeling & simulation analysis.

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Authors and Affiliations

  1. Drug Modeling & Consulting, Dynakin, SL, Bilbao, Spain

    Valvanera Vozmediano, John C. Lukas, Nerea Leal & Mónica Rodriguez

  2. Clinical Research Department, FAES FARMA, S.A., Bilbao, Spain

    Ander Sologuren

Authors
  1. Valvanera Vozmediano
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  2. Ander Sologuren
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  3. John C. Lukas
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  4. Nerea Leal
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  5. Mónica Rodriguez
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Correspondence to Valvanera Vozmediano.

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Vozmediano, V., Sologuren, A., Lukas, J.C. et al. Model Informed Pediatric Development Applied to Bilastine: Ontogenic PK Model Development, Dose Selection for First Time in Children and PK Study Design. Pharm Res 34, 2720–2734 (2017). https://doi.org/10.1007/s11095-017-2248-6

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