The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling
Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/9/1957 |
| _version_ | 1797483560362311680 |
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| author | Karel Allegaert Mohammad Yaseen Abbasi Robin Michelet Olusola Olafuyi |
| author_facet | Karel Allegaert Mohammad Yaseen Abbasi Robin Michelet Olusola Olafuyi |
| author_sort | Karel Allegaert |
| collection | DOAJ |
| description | Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp<sup>®</sup> (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, manual infusion dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80–125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80–125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40–50%, a dose reduction of 15% is warranted in neonates, infants and children, and 25% in adolescents and adults. Conclusions: PBPK-driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, and proportionally greater in adults. Consequently, age group-specific dose reductions for propofol are required in LCO conditions. |
| first_indexed | 2024-03-09T22:49:46Z |
| format | Article |
| id | doaj.art-c9eda92e1bbf47d880044504239507de |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T22:49:46Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-c9eda92e1bbf47d880044504239507de2023-11-23T18:23:38ZengMDPI AGPharmaceutics1999-49232022-09-01149195710.3390/pharmaceutics14091957The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic ModellingKarel Allegaert0Mohammad Yaseen Abbasi1Robin Michelet2Olusola Olafuyi3Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, BelgiumDivision of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USADepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, GermanyDivision of Physiology, Pharmacology and Neurosciences, School of Life Sciences, University of Nottingham, Nottingham NGT 2TQ, UKBackground: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp<sup>®</sup> (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, manual infusion dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80–125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80–125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40–50%, a dose reduction of 15% is warranted in neonates, infants and children, and 25% in adolescents and adults. Conclusions: PBPK-driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, and proportionally greater in adults. Consequently, age group-specific dose reductions for propofol are required in LCO conditions.https://www.mdpi.com/1999-4923/14/9/1957physiologically based pharmacokinetic modellingpropofollow cardiac outputpharmacokineticsneonatedevelopmental pharmacology |
| spellingShingle | Karel Allegaert Mohammad Yaseen Abbasi Robin Michelet Olusola Olafuyi The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling Pharmaceutics physiologically based pharmacokinetic modelling propofol low cardiac output pharmacokinetics neonate developmental pharmacology |
| title | The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling |
| title_full | The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling |
| title_fullStr | The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling |
| title_full_unstemmed | The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling |
| title_short | The Impact of Low Cardiac Output on Propofol Pharmacokinetics across Age Groups—An Investigation Using Physiologically Based Pharmacokinetic Modelling |
| title_sort | impact of low cardiac output on propofol pharmacokinetics across age groups an investigation using physiologically based pharmacokinetic modelling |
| topic | physiologically based pharmacokinetic modelling propofol low cardiac output pharmacokinetics neonate developmental pharmacology |
| url | https://www.mdpi.com/1999-4923/14/9/1957 |
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