TY - JOUR A1 - Busse, David A1 - Simon, Philipp A1 - Petroff, David A1 - El-Najjar, Nahed A1 - Schmitt, Lisa A1 - Bindellini, Davide A1 - Dietrich, Arne A1 - Zeitlinger, Markus A1 - Huisinga, Wilhelm A1 - Michelet, Robin A1 - Wrigge, Hermann A1 - Kloft, Charlotte T1 - High-dosage fosfomycin results in adequate plasma and target-site exposure in morbidly obese and nonobese nonhyperfiltration patients JF - Antimicrobial agents and chemotherapy N2 - The objectives of this study were the identification in (morbidly) obese and nonobese patients of (i) the most appropriate body size descriptor for fosfomycin dose adjustments and (ii) adequacy of the currently employed dosing regimens. Plasma and target site (interstitial fluid of subcutaneous adipose tissue) concentrations after fosfomycin administration (8 g) to 30 surgery patients (15 obese/15 nonobese) were obtained from a prospective clinical trial. After characterization of plasma and microdialysis-derived target site pharmacokinetics via population analysis, short-term infusions of fosfomycin 3 to 4 times daily were simulated. The adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target attainment (PTA) analysis based on the unbound drug-related targets of an %fT(>= MIC) (the fraction of time that unbound fosfomycin concentrations exceed the MIC during 24 h) of 70 and an fAUC(0-24h)/MIC (the area under the concentration-time curve from 0 to 24 h for the unbound fraction of fosfomycin relative to the MIC) of 40.8 to 83.3. Lean body weight, fat mass, and creatinine clearance calculated via adjusted body weight (ABW) (CLCRCG_ABW) of all patients (body mass index [BMI] = 20.1 to 52.0 kg/m(2)) explained a considerable proportion of between-patient pharmacokinetic variability (up to 31.0% relative reduction). The steady-state unbound target site/plasma concentration ratio was 26.3% lower in (morbidly) obese than nonobese patients. For infections with fosfomycin-susceptible pathogens (MIC <= 16 mg/L), intermittent "high-dosage" intravenous (i.v.) fosfomycin (8 g, three times daily) was sufficient to treat patients with a CLCRCG_ABW of,130 mL/min, irrespective of the pharmacokinetic/pharmacodynamic indices considered. For infections by Pseudomonas aeruginosa with a MIC of 32 mg/L, when the index fAUC0-24h/MIC is applied, fosfomycin might represent a promising treatment option in obese and nonobese patients, especially in combination therapy to complement beta-lactams, in which carbapenem-resistant P. aeruginosa is critical. In conclusion, fosfomycin showed excellent target site penetration in obese and nonobese patients. Dosing should be guided by renal function rather than obesity status. KW - population pharmacokinetics KW - pharmacodynamics KW - fosfomycin KW - obesity KW - adipose tissue KW - interstitial space fluid KW - microdialysis KW - anti-infective KW - probability of target attainment Y1 - 2022 U6 - https://doi.org/10.1128/aac.02302-21 SN - 0066-4804 SN - 1098-6596 VL - 66 IS - 6 PB - American Society for Microbiology CY - Washington ER - TY - JOUR A1 - Stachanow, Viktoria A1 - Neumann, Uta A1 - Blankenstein, Oliver A1 - Bindellini, Davide A1 - Melin, Johanna A1 - Ross, Richard A1 - Whitaker, Martin J. J. A1 - Huisinga, Wilhelm A1 - Michelet, Robin A1 - Kloft, Charlotte T1 - Exploring dried blood spot cortisol concentrations as an alternative for monitoring pediatric adrenal insufficiency patients BT - a model-based analysis JF - Frontiers in pharmacology N2 - 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. KW - adrenal insufficiency KW - cortisol KW - dried blood spots KW - pediatrics KW - pharmacokinetics KW - binding KW - association KW - red blood cells Y1 - 2022 U6 - https://doi.org/10.3389/fphar.2022.819590 SN - 1663-9812 VL - 13 PB - Frontiers Media CY - Lausanne ER - TY - JOUR A1 - Michelet, Robin A1 - Bindellini, Davide A1 - Melin, Johanna A1 - Neumann, Uta A1 - Blankenstein, Oliver A1 - Huisinga, Wilhelm A1 - Johnson, Trevor N. A1 - Whitaker, Martin J. A1 - Ross, Richard A1 - Kloft, Charlotte T1 - Insights in the maturational processes influencing hydrocortisone pharmacokinetics in congenital adrenal hyperplasia patients using a middle-out approach JF - Frontiers in Pharmacology N2 - 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. KW - hydrocortisone KW - congenital adrenal hyperplasia KW - population pharmacokinetics KW - middle-out approach KW - pediatrics KW - physiologically-based pharmacokinetics (PBPK) KW - non-linear mixed effects modelling (NLME); KW - maturation Y1 - 2023 U6 - https://doi.org/10.3389/fphar.2022.1090554 SN - 1663-9812 VL - 13 PB - Frontiers Media CY - Lausanne ER -