@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{EhmannZollerMinichmayretal.2017,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Scharf, Christina and Maier, Barbara and Schmitt, Maximilian V. and Hartung, Niklas and Huisinga, Wilhelm and Vogeser, Michael and Frey, Lorenz and Zander, Johannes and Kloft, Charlotte},
  title     = {Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients},
  series = {Critical care},
  volume    = {21},
  journal   = {Critical care},
  publisher = {BioMed Central},
  address   = {London},
  issn      = {1466-609X},
  doi       = {10.1186/s13054-017-1829-4},
  pages     = {14},
  year      = {2017},
  abstract  = {Background: Severe bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application. Methods: A prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100\% T->MIC, 50\% T->4xMIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment. Results: Large inter-and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100\% T->MIC was merely 48.4\% and 20.6\%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50\% T->4xMIC. A hyperbolic relationship between CLCRCG (25-255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C-8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment). Conclusions: The investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy-and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.},
  language  = {en}
}