Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use


The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time.

Publication DOI:
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Funding Information: This research was funded by Aston University and Proveca Ltd., No. 1 Spinningfields, Quay Street, Manchester, M3 3JE, UK.
Additional Information: Copyright © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( Funding: This research was funded by Aston University and Proveca Ltd., No. 1 Spinningfields, Quay Street, Manchester, M3 3JE, UK.
Uncontrolled Keywords: PBPK,adherence,age-appropriate,mini-tablets,modified release,paediatrics,pharmacokinetics,Pharmaceutical Science
Publication ISSN: 1999-4923
Last Modified: 13 Jun 2024 07:29
Date Deposited: 17 Feb 2023 09:01
Full Text Link:
Related URLs: https://www.mdp ... 9-4923/15/2/556 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-02-07
Published Online Date: 2023-02-07
Accepted Date: 2023-01-28
Authors: Khan, Dilawar
Badhan, Raj (ORCID Profile 0000-0002-0904-9324)
Kirby, Daniel J. (ORCID Profile 0000-0002-0878-2620)
Bryson, Simon
Shah, Maryam
Mohammed, Afzal Rahman (ORCID Profile 0000-0002-5212-3040)



Version: Published Version

License: Creative Commons Attribution

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