Modelling Hydrocortisone Pharmacokinetics on a Subcutaneous Pulsatile Infusion Replacement Strategy in Patients with Adrenocortical Insufficiency
Ioannis G. Violaris,
Konstantinos Kalafatakis,
Eder Zavala,
Ioannis G. Tsoulos,
Theodoros Lampros,
Stafford L. Lightman,
Markos G. Tsipouras,
Nikolaos Giannakeas,
Alexandros Tzallas,
Georgina M. Russell
Affiliations
Ioannis G. Violaris
Department of Electrical and Computer Engineering, University of Western Macedonia, 50131 Kozani, Greece
Konstantinos Kalafatakis
Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK
Eder Zavala
Centre for Systems Modelling and Quantitative Biomedicine, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Ioannis G. Tsoulos
Department of Informatics & Telecommunications, School of Informatics & Telecommunications, University of Ioannina, 47100 Arta, Greece
Theodoros Lampros
Department of Informatics & Telecommunications, School of Informatics & Telecommunications, University of Ioannina, 47100 Arta, Greece
Stafford L. Lightman
Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK
Markos G. Tsipouras
Department of Electrical and Computer Engineering, University of Western Macedonia, 50131 Kozani, Greece
Nikolaos Giannakeas
Department of Informatics & Telecommunications, School of Informatics & Telecommunications, University of Ioannina, 47100 Arta, Greece
Alexandros Tzallas
Department of Informatics & Telecommunications, School of Informatics & Telecommunications, University of Ioannina, 47100 Arta, Greece
Georgina M. Russell
Laboratories of Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, UK
In the context of glucocorticoid (GC) therapeutics, recent studies have utilised a subcutaneous hydrocortisone (HC) infusion pump programmed to deliver multiple HC pulses throughout the day, with the purpose of restoring normal circadian and ultradian GC rhythmicity. A key challenge for the advancement of novel HC replacement therapies is the calibration of infusion pumps against cortisol levels measured in blood. However, repeated blood sampling sessions are enormously labour-intensive for both examiners and examinees. These sessions also have a cost, are time consuming and are occasionally unfeasible. To address this, we developed a pharmacokinetic model approximating the values of plasma cortisol levels at any point of the day from a limited number of plasma cortisol measurements. The model was validated using the plasma cortisol profiles of 9 subjects with disrupted endogenous GC synthetic capacity. The model accurately predicted plasma cortisol levels (mean absolute percentage error of 14%) when only four plasma cortisol measurements were provided. Although our model did not predict GC dynamics when HC was administered in a way other than subcutaneously or in individuals whose endogenous capacity to produce GCs is intact, it was found to successfully be used to support clinical trials (or practice) involving subcutaneous HC delivery in patients with reduced endogenous capacity to synthesize GCs.
