Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis
Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS)...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.819590/full |
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| author | Viktoria Stachanow Viktoria Stachanow Uta Neumann Oliver Blankenstein Oliver Blankenstein Davide Bindellini Davide Bindellini Johanna Melin Johanna Melin Richard Ross Martin J. Whitaker Wilhelm Huisinga Robin Michelet Charlotte Kloft |
| author_facet | Viktoria Stachanow Viktoria Stachanow Uta Neumann Oliver Blankenstein Oliver Blankenstein Davide Bindellini Davide Bindellini Johanna Melin Johanna Melin Richard Ross Martin J. Whitaker Wilhelm Huisinga Robin Michelet Charlotte Kloft |
| author_sort | Viktoria Stachanow |
| collection | DOAJ |
| description | Congenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples. |
| first_indexed | 2024-12-13T01:42:02Z |
| format | Article |
| id | doaj.art-639672d647694bf1af2176e7479854f8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-13T01:42:02Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-639672d647694bf1af2176e7479854f82022-12-22T00:03:43ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-03-011310.3389/fphar.2022.819590819590Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based AnalysisViktoria Stachanow0Viktoria Stachanow1Uta Neumann2Oliver Blankenstein3Oliver Blankenstein4Davide Bindellini5Davide Bindellini6Johanna Melin7Johanna Melin8Richard Ross9Martin J. Whitaker10Wilhelm Huisinga11Robin Michelet12Charlotte Kloft13Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, GermanyGraduate Research Training Program PharMetrX, Berlin, GermanyPediatric Endocrinology, Charité-Universitätsmedizin, Berlin, GermanyPediatric Endocrinology, Charité-Universitätsmedizin, Berlin, GermanyLabor Berlin, Charité Vivantes GmbH, Berlin, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, GermanyGraduate Research Training Program PharMetrX, Berlin, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, GermanyGraduate Research Training Program PharMetrX, Berlin, GermanyDiurnal Limited, Cardiff, United KingdomDiurnal Limited, Cardiff, United KingdomInstitute of Mathematics, Universität Potsdam, Potsdam, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, GermanyDepartment of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, GermanyCongenital adrenal hyperplasia (CAH) is the most common form of adrenal insufficiency in childhood; it requires cortisol replacement therapy with hydrocortisone (HC, synthetic cortisol) from birth and therapy monitoring for successful treatment. In children, the less invasive dried blood spot (DBS) sampling with whole blood including red blood cells (RBCs) provides an advantageous alternative to plasma sampling. Potential differences in binding/association processes between plasma and DBS however need to be considered to correctly interpret DBS measurements for therapy monitoring. While capillary DBS samples would be used in clinical practice, venous cortisol DBS samples from children with adrenal insufficiency were analyzed due to data availability and to directly compare and thus understand potential differences between venous DBS and plasma. A previously published HC plasma pharmacokinetic (PK) model was extended by leveraging these DBS concentrations. In addition to previously characterized binding of cortisol to albumin (linear process) and corticosteroid-binding globulin (CBG; saturable process), DBS data enabled the characterization of a linear cortisol association with RBCs, and thereby providing a quantitative link between DBS and plasma cortisol concentrations. The ratio between the observed cortisol plasma and DBS concentrations varies highly from 2 to 8. Deterministic simulations of the different cortisol binding/association fractions demonstrated that with higher blood cortisol concentrations, saturation of cortisol binding to CBG was observed, leading to an increase in all other cortisol binding fractions. In conclusion, a mathematical PK model was developed which links DBS measurements to plasma exposure and thus allows for quantitative interpretation of measurements of DBS samples.https://www.frontiersin.org/articles/10.3389/fphar.2022.819590/fulladrenal insufficiencycortisoldried blood spotspediatricspharmacokineticsbinding |
| spellingShingle | Viktoria Stachanow Viktoria Stachanow Uta Neumann Oliver Blankenstein Oliver Blankenstein Davide Bindellini Davide Bindellini Johanna Melin Johanna Melin Richard Ross Martin J. Whitaker Wilhelm Huisinga Robin Michelet Charlotte Kloft Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis Frontiers in Pharmacology adrenal insufficiency cortisol dried blood spots pediatrics pharmacokinetics binding |
| title | Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis |
| title_full | Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis |
| title_fullStr | Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis |
| title_full_unstemmed | Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis |
| title_short | Exploring Dried Blood Spot Cortisol Concentrations as an Alternative for Monitoring Pediatric Adrenal Insufficiency Patients: A Model-Based Analysis |
| title_sort | exploring dried blood spot cortisol concentrations as an alternative for monitoring pediatric adrenal insufficiency patients a model based analysis |
| topic | adrenal insufficiency cortisol dried blood spots pediatrics pharmacokinetics binding |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.819590/full |
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