Population pharmacokinetic modelling of rupatadine solution in 6-11 year olds and optimisation of the experimental design in younger children

PLoS One. 2017 Apr 18;12(4):e0176091. doi: 10.1371/journal.pone.0176091. eCollection 2017.

Abstract

Aims: To optimise a pharmacokinetic (PK) study design of rupatadine for 2-5 year olds by using a population PK model developed with data from a study in 6-11 year olds. The design optimisation was driven by the need to avoid children's discomfort in the study.

Methods: PK data from 6-11 year olds with allergic rhinitis available from a previous study were used to construct a population PK model which we used in simulations to assess the dose to administer in a study in 2-5 year olds. In addition, an optimal design approach was used to determine the most appropriate number of sampling groups, sampling days, total samples and sampling times.

Results: A two-compartmental model with first-order absorption and elimination, with clearance dependent on weight adequately described the PK of rupatadine for 6-11 year olds. The dose selected for a trial in 2-5 year olds was 2.5 mg, as it provided a Cmax below the 3 ng/ml threshold. The optimal study design consisted of four groups of children (10 children each), a maximum sampling window of 2 hours in two clinic visits for drawing three samples on day 14 and one on day 28 coinciding with the final examination of the study.

Conclusions: A PK study design was optimised in order to prioritise avoidance of discomfort for enrolled 2-5 year olds by taking only four blood samples from each child and minimising the length of hospital stays.

MeSH terms

  • Algorithms
  • Anti-Allergic Agents / administration & dosage
  • Anti-Allergic Agents / blood
  • Anti-Allergic Agents / pharmacokinetics*
  • Anti-Allergic Agents / therapeutic use
  • Child
  • Child, Preschool
  • Computer Simulation
  • Cyproheptadine / administration & dosage
  • Cyproheptadine / analogs & derivatives*
  • Cyproheptadine / blood
  • Cyproheptadine / pharmacokinetics
  • Cyproheptadine / therapeutic use
  • Female
  • Humans
  • Male
  • Models, Biological
  • Research Design
  • Rhinitis, Allergic / drug therapy*

Substances

  • Anti-Allergic Agents
  • rupatadine
  • Cyproheptadine

Grant support

This work was financed by J. Uriach y Compañía, S.A. and ES and II participated in the study design, data colection and preparation of the manuscript. Marta Valle was supported by a grant (FIS CP04/00121) from the Spanish Health Ministry in collaboration with Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau, Barcelona; she and Jordi Riba are members of CIBERSAM (funded by the Spanish Health Ministry, Instituto de Salud Carlos III). FEDER. CERCA Programme/Generalitat de Catalunya. Javier Estévez was supported by a grant from the Spanish Ministry of Health, Project TRA-076; he was also partially supported by the Alban Program, the European Union Program of High Level Scholarships for Latin America (scholarship No. E06D101499CU). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.