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 pr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/2/556 |
| _version_ | 1827755894846259200 |
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| author | Dilawar Khan Raj Badhan Daniel J. Kirby Simon Bryson Maryam Shah Afzal Rahman Mohammed |
| author_facet | Dilawar Khan Raj Badhan Daniel J. Kirby Simon Bryson Maryam Shah Afzal Rahman Mohammed |
| author_sort | Dilawar Khan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T08:16:26Z |
| format | Article |
| id | doaj.art-06ba2c144adc41f5bf7703dd1497da8a |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T08:16:26Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-06ba2c144adc41f5bf7703dd1497da8a2023-11-16T22:41:31ZengMDPI AGPharmaceutics1999-49232023-02-0115255610.3390/pharmaceutics15020556Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric UseDilawar Khan0Raj Badhan1Daniel J. Kirby2Simon Bryson3Maryam Shah4Afzal Rahman Mohammed5Aston Pharmacy School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKAston Pharmacy School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKAston Pharmacy School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKProveca Ltd., No. 1 Spinningfields, Quay Street, Manchester M3 3JE, UKProveca Ltd., No. 1 Spinningfields, Quay Street, Manchester M3 3JE, UKAston Pharmacy School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UKThe 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.https://www.mdpi.com/1999-4923/15/2/556paediatricsPBPKpharmacokineticsage-appropriatemini-tabletsmodified release |
| spellingShingle | Dilawar Khan Raj Badhan Daniel J. Kirby Simon Bryson Maryam Shah Afzal Rahman Mohammed Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use Pharmaceutics paediatrics PBPK pharmacokinetics age-appropriate mini-tablets modified release |
| title | Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use |
| title_full | Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use |
| title_fullStr | Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use |
| title_full_unstemmed | Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use |
| title_short | Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use |
| title_sort | virtual clinical trials guided design of an age appropriate formulation and dosing strategy of nifedipine for paediatric use |
| topic | paediatrics PBPK pharmacokinetics age-appropriate mini-tablets modified release |
| url | https://www.mdpi.com/1999-4923/15/2/556 |
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