Model-Informed Dose Optimization of Spironolactone in Neonates and Infants
<b>Background/Objectives</b>: Spironolactone (SP) has been used off-label in pediatrics since its approval, but its use is challenged by limited pharmacokinetic (PK) data in adults and especially in children. <b>Methods</b>: Physiologically based pharmacokinetic (PBPK) models...
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MDPI AG
2025-03-01
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| author | Amira Soliman Leandro F. Pippa Jana Lass Stephanie Leroux Valvanera Vozmediano Natalia V. de Moraes |
| author_facet | Amira Soliman Leandro F. Pippa Jana Lass Stephanie Leroux Valvanera Vozmediano Natalia V. de Moraes |
| author_sort | Amira Soliman |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Spironolactone (SP) has been used off-label in pediatrics since its approval, but its use is challenged by limited pharmacokinetic (PK) data in adults and especially in children. <b>Methods</b>: Physiologically based pharmacokinetic (PBPK) models for SP and its active metabolites, canrenone (CAN) and 7α thio-methyl spironolactone (TMS), in adults were developed. These models aim to enhance understanding of SP’s PK and provide a basis for predicting PK and optimizing SP dosing in infants and neonates. Given SP’s complex metabolism, we assumed complete conversion to CAN and TMS by CES1 enzymes, fitting CES1-mediated metabolism to the parent-metabolite model using PK data. We incorporated ontogeny for CES1 and CYP3A4 and other age-related physiological changes into the model to anticipate PK in the pediatric population. <b>Results</b>: The PBPK models for SP, CAN, and TMS accurately captured the observed PK data in healthy adults across various dosing regimens, including the impact of food on drug exposure. The pediatric PBPK model was evaluated using PK data from infants and neonates. Simulations indicate that 2.5 mg/kg in 6-month to 2-year infants and 2 mg/kg in 1–6-months infants matched the total unbound systemic exposure equivalent to the standard recommended daily maintenance dose of 100 mg in adults for treating edema. <b>Conclusions</b>: The developed PBPK model provides valuable insights for dosing decisions and optimizing therapeutic outcomes, especially in populations where clinical studies are challenging. |
| format | Article |
| id | doaj-art-a51b61d8e58a4c87b020dade8bd49113 |
| institution | OA Journals |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-a51b61d8e58a4c87b020dade8bd491132025-08-20T02:10:24ZengMDPI AGPharmaceuticals1424-82472025-03-0118335510.3390/ph18030355Model-Informed Dose Optimization of Spironolactone in Neonates and InfantsAmira Soliman0Leandro F. Pippa1Jana Lass2Stephanie Leroux3Valvanera Vozmediano4Natalia V. de Moraes5Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL 32827, USACenter for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL 32827, USAInstitute of Pharmacy, University of Tartu, 50411 Tartu, EstoniaCHU Rennes, University Hospital Rennes, Inserm, EHESP, Irset—UMR_S 1085, F-35000 Rennes, FranceCenter for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL 32827, USACenter for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, University of Florida, Orlando, FL 32827, USA<b>Background/Objectives</b>: Spironolactone (SP) has been used off-label in pediatrics since its approval, but its use is challenged by limited pharmacokinetic (PK) data in adults and especially in children. <b>Methods</b>: Physiologically based pharmacokinetic (PBPK) models for SP and its active metabolites, canrenone (CAN) and 7α thio-methyl spironolactone (TMS), in adults were developed. These models aim to enhance understanding of SP’s PK and provide a basis for predicting PK and optimizing SP dosing in infants and neonates. Given SP’s complex metabolism, we assumed complete conversion to CAN and TMS by CES1 enzymes, fitting CES1-mediated metabolism to the parent-metabolite model using PK data. We incorporated ontogeny for CES1 and CYP3A4 and other age-related physiological changes into the model to anticipate PK in the pediatric population. <b>Results</b>: The PBPK models for SP, CAN, and TMS accurately captured the observed PK data in healthy adults across various dosing regimens, including the impact of food on drug exposure. The pediatric PBPK model was evaluated using PK data from infants and neonates. Simulations indicate that 2.5 mg/kg in 6-month to 2-year infants and 2 mg/kg in 1–6-months infants matched the total unbound systemic exposure equivalent to the standard recommended daily maintenance dose of 100 mg in adults for treating edema. <b>Conclusions</b>: The developed PBPK model provides valuable insights for dosing decisions and optimizing therapeutic outcomes, especially in populations where clinical studies are challenging.https://www.mdpi.com/1424-8247/18/3/355PBPKinfantspediatricsspironolactonedose optimization |
| spellingShingle | Amira Soliman Leandro F. Pippa Jana Lass Stephanie Leroux Valvanera Vozmediano Natalia V. de Moraes Model-Informed Dose Optimization of Spironolactone in Neonates and Infants Pharmaceuticals PBPK infants pediatrics spironolactone dose optimization |
| title | Model-Informed Dose Optimization of Spironolactone in Neonates and Infants |
| title_full | Model-Informed Dose Optimization of Spironolactone in Neonates and Infants |
| title_fullStr | Model-Informed Dose Optimization of Spironolactone in Neonates and Infants |
| title_full_unstemmed | Model-Informed Dose Optimization of Spironolactone in Neonates and Infants |
| title_short | Model-Informed Dose Optimization of Spironolactone in Neonates and Infants |
| title_sort | model informed dose optimization of spironolactone in neonates and infants |
| topic | PBPK infants pediatrics spironolactone dose optimization |
| url | https://www.mdpi.com/1424-8247/18/3/355 |
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