@article{MelinHartungParraGuillenetal.2019,
  author    = {Melin, Johanna Stina Elisabet and Hartung, Niklas and Parra-Guillen, Zinnia Patricia and Whitaker, Martin J. and Ross, Richard J. and Kloft, Charlotte},
  title     = {The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing},
  series = {Clinical endocrinology},
  volume    = {91},
  journal   = {Clinical endocrinology},
  number    = {1},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0300-0664},
  doi       = {10.1111/cen.13969},
  pages     = {33 -- 40},
  year      = {2019},
  abstract  = {Context Optimization of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. Objective A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. Design and Methods CBG was measured over 24 hours in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. Results The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 mu g/mL and interindividual variability 11.9\%; the amplitude for the 24 and 12 hours cosine functions were relatively small (24 hours: 5.53\%, 12 hours: 2.87\%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (<= 12.2\%), also regarding the free cortisol concentration and free fraction (<= 11.7\%). Conclusions Corticosteroid-binding globulin has a circadian rhythm but the difference in cortisol exposure is <= 12.2\% between times of highest and lowest CBG concentrations; therefore, hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.},
  language  = {en}
}
@article{MelinParraGuillenHartungetal.2018,
  author    = {Melin, Johanna and Parra-Guillen, Zinnia Patricia and Hartung, Niklas and Huisinga, Wilhelm and Ross, Richard J. and Whitaker, Martin J. and Kloft, Charlotte},
  title     = {Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults},
  series = {Clinical Pharmacokinetics},
  volume    = {57},
  journal   = {Clinical Pharmacokinetics},
  number    = {4},
  publisher = {Springer},
  address   = {Northcote},
  issn      = {0312-5963},
  doi       = {10.1007/s40262-017-0575-8},
  pages     = {515 -- 527},
  year      = {2018},
  abstract  = {Background and objective Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort (R) oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Methods Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort (R) or 20 mg of Infacort (R)/hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Results Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline (cort),15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing < 20 kg. Conclusions Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing < 20 kg.},
  language  = {en}
}
@article{StachanowNeumannBlankensteinetal.2022,
  author    = {Stachanow, Viktoria and Neumann, Uta and Blankenstein, Oliver and Bindellini, Davide and Melin, Johanna and Ross, Richard and Whitaker, Martin J. J. and Huisinga, Wilhelm and Michelet, Robin and Kloft, Charlotte},
  title     = {Exploring dried blood spot cortisol concentrations as an alternative for monitoring pediatric adrenal insufficiency patients},
  series = {Frontiers in pharmacology},
  volume    = {13},
  journal   = {Frontiers in pharmacology},
  publisher = {Frontiers Media},
  address   = {Lausanne},
  issn      = {1663-9812},
  doi       = {10.3389/fphar.2022.819590},
  pages     = {8},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{MicheletBindelliniMelinetal.2023,
  author    = {Michelet, Robin and Bindellini, Davide and Melin, Johanna and Neumann, Uta and Blankenstein, Oliver and Huisinga, Wilhelm and Johnson, Trevor N. and Whitaker, Martin J. and Ross, Richard and Kloft, Charlotte},
  title     = {Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach},
  series = {Frontiers in Pharmacology},
  volume    = {13},
  journal   = {Frontiers in Pharmacology},
  publisher = {Frontiers Media},
  address   = {Lausanne},
  issn      = {1663-9812},
  doi       = {10.3389/fphar.2022.1090554},
  pages     = {14},
  year      = {2023},
  abstract  = {Introduction: Hydrocortisone is the standard of care in cortisol replacement therapy for congenital adrenal hyperplasia patients. Challenges in mimicking cortisol circadian rhythm and dosing individualization can be overcome by the support of mathematical modelling. Previously, a non-linear mixed-effects (NLME) model was developed based on clinical hydrocortisone pharmacokinetic (PK) pediatric and adult data. Additionally, a physiologically-based pharmacokinetic (PBPK) model was developed for adults and a pediatric model was obtained using maturation functions for relevant processes. In this work, a middle-out approach was applied. The aim was to investigate whether PBPK-derived maturation functions could provide a better description of hydrocortisone PK inter-individual variability when implemented in the NLME framework, with the goal of providing better individual predictions towards precision dosing at the patient level. Methods: Hydrocortisone PK data from 24 adrenal insufficiency pediatric patients and 30 adult healthy volunteers were used for NLME model development, while the PBPK model and maturation functions of clearance and cortisol binding globulin (CBG) were developed based on previous studies published in the literature. Results: Clearance (CL) estimates from both approaches were similar for children older than 1 year (CL/F increasing from around 150 L/h to 500 L/h), while CBG concentrations differed across the whole age range (CBG(NLME) stable around 0.5 mu M vs. steady increase from 0.35 to 0.8 mu M for CBG (PBPK)). PBPK-derived maturation functions were subsequently included in the NLME model. After inclusion of the maturation functions, none, a part of, or all parameters were re-estimated. However, the inclusion of CL and/or CBG maturation functions in the NLME model did not result in improved model performance for the CL maturation function (\& UDelta;OFV > -15.36) and the re-estimation of parameters using the CBG maturation function most often led to unstable models or individual CL prediction bias. Discussion: Three explanations for the observed discrepancies could be postulated, i) non-considered maturation of processes such as absorption or first-pass effect, ii) lack of patients between 1 and 12 months, iii) lack of correction of PBPK CL maturation functions derived from urinary concentration ratio data for the renal function relative to adults. These should be investigated in the future to determine how NLME and PBPK methods can work towards deriving insights into pediatric hydrocortisone PK.},
  language  = {en}
}