@article{MaierWiljesHartungetal.2022,
  author    = {Maier, Corinna Sabrina and Wiljes, Jana de and Hartung, Niklas and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {A continued learning approach for model-informed precision dosing},
  series = {CPT: pharmacometrics \& systems pharmacology},
  volume    = {11},
  journal   = {CPT: pharmacometrics \& systems pharmacology},
  number    = {2},
  publisher = {London},
  address   = {Nature Publ. Group},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12745},
  pages     = {185 -- 198},
  year      = {2022},
  abstract  = {Model-informed precision dosing (MIPD) is a quantitative dosing framework that combines prior knowledge on the drug-disease-patient system with patient data from therapeutic drug/ biomarker monitoring (TDM) to support individualized dosing in ongoing treatment. Structural models and prior parameter distributions used in MIPD approaches typically build on prior clinical trials that involve only a limited number of patients selected according to some exclusion/inclusion criteria. Compared to the prior clinical trial population, the patient population in clinical practice can be expected to also include altered behavior and/or increased interindividual variability, the extent of which, however, is typically unknown. Here, we address the question of how to adapt and refine models on the level of the model parameters to better reflect this real-world diversity. We propose an approach for continued learning across patients during MIPD using a sequential hierarchical Bayesian framework. The approach builds on two stages to separate the update of the individual patient parameters from updating the population parameters. Consequently, it enables continued learning across hospitals or study centers, because only summary patient data (on the level of model parameters) need to be shared, but no individual TDM data. We illustrate this continued learning approach with neutrophil-guided dosing of paclitaxel. The present study constitutes an important step toward building confidence in MIPD and eventually establishing MIPD increasingly in everyday therapeutic use.},
  language  = {en}
}
@article{EdlundGrisicSteenholdtetal.2019,
  author    = {Edlund, Helena and Grisic, Ana-Marija and Steenholdt, Casper and Ainsworth, Mark Andrew and Brynskov, Torn and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure},
  series = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology},
  volume    = {41},
  journal   = {Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology},
  number    = {2},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0163-4356},
  doi       = {10.1097/FTD.0000000000000590},
  pages     = {235 -- 242},
  year      = {2019},
  abstract  = {Background: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. Methods: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. Results: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. Conclusions: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.},
  language  = {en}
}
@misc{MaierHartungdeWiljesetal.2020,
  author    = {Maier, Corinna and Hartung, Niklas and de Wiljes, Jana and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy},
  series = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe},
  journal   = {Postprints der Universit{\"a}t Potsdam : Mathematisch Naturwissenschaftliche Reihe},
  number    = {827},
  issn      = {1866-8372},
  doi       = {10.25932/publishup-44550},
  url       = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-445500},
  pages     = {14},
  year      = {2020},
  abstract  = {An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas.},
  language  = {en}
}
@article{MaierHartungdeWiljesetal.2020,
  author    = {Maier, Corinna and Hartung, Niklas and de Wiljes, Jana and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy},
  series = {CPT: Pharmacometrics \& Systems Pharmacology},
  volume    = {XX},
  journal   = {CPT: Pharmacometrics \& Systems Pharmacology},
  publisher = {Nature Publ. Group},
  address   = {London},
  issn      = {2163-8306},
  doi       = {10.1002/psp4.12492},
  pages     = {12},
  year      = {2020},
  abstract  = {An essential component of therapeutic drug/biomarker monitoring (TDM) is to combine patient data with prior knowledge for model-based predictions of therapy outcomes. Current Bayesian forecasting tools typically rely only on the most probable model parameters (maximum a posteriori (MAP) estimate). This MAP-based approach, however, does neither necessarily predict the most probable outcome nor does it quantify the risks of treatment inefficacy or toxicity. Bayesian data assimilation (DA) methods overcome these limitations by providing a comprehensive uncertainty quantification. We compare DA methods with MAP-based approaches and show how probabilistic statements about key markers related to chemotherapy-induced neutropenia can be leveraged for more informative decision support in individualized chemotherapy. Sequential Bayesian DA proved to be most computationally efficient for handling interoccasion variability and integrating TDM data. For new digital monitoring devices enabling more frequent data collection, these features will be of critical importance to improve patient care decisions in various therapeutic areas.},
  language  = {en}
}
@misc{KrauseKloftHuisingaetal.2019,
  author    = {Krause, Andreas and Kloft, Charlotte and Huisinga, Wilhelm and Karlsson, Mats and Pinheiro, Jos{\´e} and Bies, Robert and Rogers, James and Mentr{\´e}, France and Musser, Bret J.},
  title     = {Comment on Jaki et al., A proposal for a new PhD level curriculum on quantitative methods for drug development},
  series = {Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry},
  volume    = {18},
  journal   = {Pharmaceutical statistics : the journal of applied statistics in the pharmaceutical industry},
  number    = {3},
  publisher = {Wiley},
  address   = {Hoboken},
  organization    = {ASA Special Interest Grp Stat Phar ASA Special Interest Grp Stat Phar},
  issn      = {1539-1604},
  pages     = {278 -- 281},
  year      = {2019},
  language  = {en}
}
@article{EhmannZollerMinichmayretal.2019,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Scharf, Christina and Huisinga, Wilhelm and Zander, Johannes and Kloft, Charlotte},
  title     = {Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis},
  series = {International journal of antimicrobial agents},
  volume    = {54},
  journal   = {International journal of antimicrobial agents},
  number    = {3},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0924-8579},
  doi       = {10.1016/j.ijantimicag.2019.06.016},
  pages     = {309 -- 317},
  year      = {2019},
  abstract  = {Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharma-cokinetic (PK) modelling was performed in NONMEM (R) 7.3 based on densely sampled meropenem serum samples (n(patients) = 48; n(samples) =1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCRCG ) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCRCG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3((-MIC)), pathogen and susceptibility known; L3((+MIC)), MIC known). Whereas patients with higher CLCRCG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information. (C) 2019 Published by Elsevier B.V.},
  language  = {en}
}
@article{MinichmayrRobertsFreyetal.2018,
  author    = {Minichmayr, Iris K. and Roberts, Jason A. and Frey, Otto R. and Roehr, Anka C. and Kloft, Charlotte and Brinkmann, Alexander},
  title     = {Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model},
  series = {Journal of Antimicrobial Chemotherapy},
  volume    = {73},
  journal   = {Journal of Antimicrobial Chemotherapy},
  number    = {5},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0305-7453},
  doi       = {10.1093/jac/dkx526},
  pages     = {1330 -- 1339},
  year      = {2018},
  abstract  = {Background: Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients. Objectives: To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function. Methods: A population pharmacokinetic model was developed in NONMEM (R) 7.3 based on steady-state meropenem concentrations (C-ss) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRcG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90\% of the patients. Probability of target attainment was determined for efficacy (C-ss >= 8 mg/L) and potentially increased likelihood of adverse drug reactions (C-ss >32 mg/L). Results: In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P-0.05 - P-0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/ 3940 mg were required to reach a target C-ss = 8 mg/L in 90\% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions (<0.5\%) was associated with these doses. Conclusions: A dosing nomogram was developed for continuous-infusion meropenem based on renal function in a critically ill population.},
  language  = {en}
}
@misc{EhmannZollerMinichmayretal.2018,
  author    = {Ehmann, Lisa and Zoller, Michael and Minichmayr, Iris K. and Schmitt, Maximilian V. and Hartung, Niklas and Huisinga, Wilhelm and Zander, Johannes and Kloft, Charlotte},
  title     = {Development of a tool to identify intensive care patients at risk of meropenem therapy failure},
  series = {International Journal of Clinical Pharmacy},
  volume    = {40},
  journal   = {International Journal of Clinical Pharmacy},
  number    = {1},
  publisher = {Springer},
  address   = {Dordrecht},
  issn      = {2210-7703},
  pages     = {317 -- 317},
  year      = {2018},
  language  = {en}
}
@article{ScharfWeineltSchroederetal.2022,
  author    = {Scharf, Christina and Weinelt, Ferdinand Anton and Schroeder, Ines and Paal, Michael and Weigand, Michael and Zoller, Michael and Irlbeck, Michael and Kloft, Charlotte and Briegel, Josef and Liebchen, Uwe},
  title     = {Does the cytokine adsorber CytoSorb (R) reduce vancomycin exposure in critically ill patients with sepsis or septic shock?},
  series = {Annals of intensive care},
  volume    = {12},
  journal   = {Annals of intensive care},
  number    = {1},
  publisher = {Springer},
  address   = {Heidelberg},
  issn      = {2110-5820},
  doi       = {10.1186/s13613-022-01017-5},
  pages     = {8},
  year      = {2022},
  abstract  = {Background: Hemadsorption of cytokines is used in critically ill patients with sepsis or septic shock. Concerns have been raised that the cytokine adsorber CytoSorb (R) unintentionally adsorbs vancomycin. This study aimed to quantify vancomycin elimination by CytoSorb (R) . Methods: Critically ill patients with sepsis or septic shock receiving continuous renal replacement therapy and CytoSorb (R) treatment during a prospective observational study were included in the analysis. Vancomycin pharmacokinetics was characterized using population pharmacokinetic modeling. Adsorption of vancomycin by the CytoSorb (R) was investigated as linear or saturable process. The final model was used to derive dosing recommendations based on stochastic simulations. Results: 20 CytoSorb (R) treatments in 7 patients (160 serum samples/24 during CytoSorb (R)-treatment, all continuous infusion) were included in the study. A classical one-compartment model, including effluent flow rate of the continuous hemodialysis as linear covariate on clearance, best described the measured concentrations (without CytoSorb (R)). Significant adsorption with a linear decrease during CytoSorb (R) treatment was identified (p <0.0001) and revealed a maximum increase in vancomycin clearance of 291\% (initially after CytoSorb (R) installation) and a maximum adsorption capacity of 572 mg. For a representative patient of our cohort a reduction of the area under the curve (AUC) by 93 mg/L*24 h during CytoSorb (R) treatment was observed. The additional administration of 500 mg vancomycin over 2 h during CytoSorb (R) attenuated the effect and revealed a negligible reduction of the AUC by 4 mg/L*24h. Conclusion: We recommend the infusion of 500 mg vancomycin over 2 h during CytoSorb (R) treatment to avoid subtherapeutic concentrations.},
  language  = {en}
}
@inproceedings{DemarisGrišićHuisingaetal.2020,
  author    = {D{\´e}maris, Alise and Grišić, Ana-Marija and Huisinga, Wilhelm and Walter, Reinisch and Kloft, Charlotte},
  title     = {Evaluation of dosing strategies of anti-TNF alpha monoclonal antibodies using pharmacokinetic modelling and simulation},
  series = {Journal of Crohn's and Colitis},
  volume    = {14},
  booktitle = {Journal of Crohn's and Colitis},
  number    = {Supp. 1},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  doi       = {10.1093/ecco-jcc/jjz203.201},
  pages     = {S171 -- S172},
  year      = {2020},
  abstract  = {Background: Anti-TNFα monoclonal antibodies (mAbs) are a well-established treatment for patients with Crohn's disease (CD). However, subtherapeutic concentrations of mAbs have been related to a loss of response during the first year of therapy1. Therefore, an appropriate dosing strategy is crucial to prevent the underexposure of mAbs for those patients. The aim of our study was to assess the impact of different dosing strategies (fixed dose or body size descriptor adapted) on drug exposure and the target concentration attainment for two different anti-TNFα mAbs: infliximab (IFX, body weight (BW)-based dosing) and certolizumab pegol (CZP, fixed dosing). For this purpose, a comprehensive pharmacokinetic (PK) simulation study was performed. Methods: A virtual population of 1000 clinically representative CD patients was generated based on the distribution of CD patient characteristics from an in-house clinical database (n = 116). Seven dosing regimens were investigated: fixed dose and per BW, lean BW (LBW), body surface area, height, body mass index and fat-free mass. The individual body size-adjusted doses were calculated from patient generated body size descriptor values. Then, using published PK models for IFX and CZP in CD patients2,3, for each patient, 1000 concentration-time profiles were simulated to consider the typical profile of a specific patient as well as the range of possible individual profiles due to unexplained PK variability across patients. For each dosing strategy, the variability in maximum and minimum mAb concentrations (Cmax and Cmin, respectively), area under the concentration-time curve (AUC) and the per cent of patients reaching target concentration were assessed during maintenance therapy. Results: For IFX and CZP, Cmin showed the highest variability between patients (CV ≈110\% and CV ≈80\%, respectively) with a similar extent across all dosing strategies. For IFX, the per cent of patients reaching the target (Cmin = 5 µg/ml) was similar across all dosing strategies (~15\%). For CZP, the per cent of patients reaching the target average concentration of 17 µg/ml ranged substantially (52-71\%), being the highest for LBW-adjusted dosing. Conclusion: By using a PK simulation approach, different dosing regimen of IFX and CZP revealed the highest variability for Cmin, the most commonly used PK parameter guiding treatment decisions, independent upon dosing regimen. Our results demonstrate similar target attainment with fixed dosing of IFX compared with currently recommended BW-based dosing. For CZP, the current fixed dosing strategy leads to comparable percentage of patients reaching target as the best performing body size-adjusted dosing (66\% vs. 71\%, respectively).},
  language  = {en}
}
@article{FuhrmannKloftHuisinga2017,
  author    = {Fuhrmann, Saskia and Kloft, Charlotte and Huisinga, Wilhelm},
  title     = {Impact of altered endogenous IgG on unspecific mAb clearance},
  series = {Journal of pharmacokinetics and pharmacodynamics},
  volume    = {44},
  journal   = {Journal of pharmacokinetics and pharmacodynamics},
  publisher = {Springer},
  address   = {New York},
  issn      = {1567-567X},
  doi       = {10.1007/s10928-017-9524-2},
  pages     = {351 -- 374},
  year      = {2017},
  abstract  = {Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data. We used a PBPK modelling approach to elucidate the influence of altered endogenous IgG concentrations on unspecific mAb clearance. To this end, we used PK data in immunodeficient mice, i.e. nude and severe combined immunodeficiency mice. To avoid impact of target-mediated clearance processes, we focussed on mAbs without affinity to a target antigen in these mice. In addition, intravenous immunoglobulin (IVIG) data of immunocompetent mice was used to study the impact of increased total IgG concentrations on unspecific therapeutic antibody clearance. The unspecific clearance is linear, whenever therapeutic IgG concentrations, i.e. mAb and IVIG concentrations are lower than FcRn; it can be non-linear if therapeutic IgG concentrations are larger than FcRn and endogenous IgG concentrations (e.g., under IVIG therapy). Unspecific mAb clearance of immunodeficient mice is effectively linear (under mAb doses as typically used in human). Studying the impact of reduced endogenous IgG concentrations on unspecific mAb clearance is of great relevance for the extrapolation to clinical species, e.g., when predicting mAb PK in immunosuppressed cancer patients.},
  language  = {en}
}
@misc{GrisicHuisingaReinischetal.2017,
  author    = {Grisic, Ana-Marija and Huisinga, Wilhelm and Reinisch, W. and Kloft, Charlotte},
  title     = {P485 Dosing infliximab in Crohn's disease},
  series = {Journal of Crohn's and Colitis},
  volume    = {11},
  journal   = {Journal of Crohn's and Colitis},
  number    = {1},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  doi       = {10.1093/ecco-jcc/jjx002.609},
  pages     = {S325 -- S326},
  year      = {2017},
  abstract  = {Background: Infliximab (IFX), an anti-TNF monoclonal antibody approved for the treatment of inflammatory bowel disease, is dosed per kg body weight (BW). However, the rationale for body size adjustment has not been unequivocally demonstrated [1], and first attempts to improve IFX therapy have been undertaken [2]. The aim of our study was to assess the impact of different dosing strategies (i.e. body size-adjusted and fixed dosing) on drug exposure and pharmacokinetic (PK) target attainment. For this purpose, a comprehensive simulation study was performed, using patient characteristics (n=116) from an in-house clinical database. Methods: IFX concentration-time profiles of 1000 virtual, clinically representative patients were generated using a previously published PK model for IFX in patients with Crohn's disease [3]. For each patient 1000 profiles accounting for PK variability were considered. The IFX exposure during maintenance treatment after the following dosing strategies was compared: i) fixed dose, and per ii) BW, iii) lean BW (LBW), iv) body surface area (BSA), v) height (HT), vi) body mass index (BMI) and vii) fat-free mass (FFM)). For each dosing strategy the variability in maximum concentration Cmax, minimum concentration Cmin (= C8weeks) and area under the concentration-time curve (AUC), as well as percent of patients achieving the PK target, Cmin=3 μg/mL [4] were assessed. Results: For all dosing strategies the variability of Cmin (CV ≈110\%) was highest, compared to Cmax and AUC, and was of similar extent regardless of dosing strategy. The proportion of patients reaching the PK target (≈⅓ was approximately equal for all dosing strategies.},
  language  = {en}
}
@misc{MuellerSchoellKloppSchulzeHuisingaetal.2019,
  author    = {M{\"u}ller-Sch{\"o}ll, A. and Klopp-Schulze, Lena and Huisinga, Wilhelm and J{\"o}rger, M. and Neven, P. and Koolen, S. L. and Mathijssen, R. H. J. and Schmidt, S. and Kloft, Charlotte},
  title     = {Patient-tailored tamoxifen dosing based on an increased quantitative understanding of its complex pharmacokinetics: A novel integrative modelling approach},
  series = {Annals of Oncology},
  volume    = {30},
  journal   = {Annals of Oncology},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0923-7534},
  pages     = {1},
  year      = {2019},
  language  = {en}
}
@article{KluweMicheletMuellerSchoelletal.2020,
  author    = {Kluwe, Franziska and Michelet, Robin and M{\"u}ller-Sch{\"o}ll, Anna and Maier, Corinna and Klopp-Schulze, Lena and van Dyk, Madele and Mikus, Gerd and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Perspectives on model-informed precision dosing in the digital health era},
  series = {Clinical pharmacology \& therapeutics},
  volume    = {109},
  journal   = {Clinical pharmacology \& therapeutics},
  number    = {1},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0009-9236},
  doi       = {10.1002/cpt.2049},
  pages     = {29 -- 36},
  year      = {2020},
  language  = {en}
}
@inproceedings{AnderssonKeuneckeEseretal.2014,
  author    = {Andersson, H. and Keunecke, A. and Eser, A. and Huisinga, Wilhelm and Reinisch, W. and Kloft, Charlotte},
  title     = {Pharmacokinetic considerations for optimising dosing regimens of a potsdam univ infliximab in patients with Crohn's disease},
  series = {JOURNAL OF CROHNS \& COLITIS},
  volume    = {8},
  booktitle = {JOURNAL OF CROHNS \& COLITIS},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  doi       = {10.1016/S1873-9946(14)60086-6},
  pages     = {S44 -- S44},
  year      = {2014},
  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{NassarHohmannMicheletetal.2022,
  author    = {Nassar, Yomna M. and Hohmann, Nicolas and Michelet, Robin and Gottwalt, Katharina and Meid, Andreas D. and Burhenne, J{\"u}rgen and Huisinga, Wilhelm and Haefeli, Walter E. and Mikus, Gerd and Kloft, Charlotte},
  title     = {Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion},
  series = {Clinical Pharmacokinetics},
  volume    = {61},
  journal   = {Clinical Pharmacokinetics},
  number    = {11},
  publisher = {Springer},
  address   = {Northcote},
  issn      = {0312-5963},
  doi       = {10.1007/s40262-022-01175-6},
  pages     = {1595 -- 1607},
  year      = {2022},
  abstract  = {Background Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. Objective We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. Methods Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. Results Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1\%, +46.7\%, -70.6\%, and -61.1\% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. Conclusions We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.},
  language  = {en}
}
@article{GrisicEserHuisingaetal.2020,
  author    = {Grisic, Ana-Marija and Eser, Alexander and Huisinga, Wilhelm and Reinisch, Walter and Kloft, Charlotte},
  title     = {Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management},
  series = {British journal of clinical pharmacology},
  volume    = {87},
  journal   = {British journal of clinical pharmacology},
  number    = {5},
  publisher = {Wiley},
  address   = {Hoboken},
  issn      = {0306-5251},
  doi       = {10.1111/bcp.14648},
  pages     = {2374 -- 2384},
  year      = {2020},
  abstract  = {Aim Quantitative and kinetic insights into the drug exposure-disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C-reactive protein (CRP) concentration. <br /> Methods Data from an investigator-initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease-related covariates were determined at the mid-term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed-effects modelling approach. An IFX exposure-CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. <br /> Results The generated quantitative model showed that IFX has the potential to inhibit up to 72\% (9\% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90\% of the maximum CRP synthesis inhibition was 18.4 mu g/mL (43\% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, >= 55\% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co-therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. <br /> Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients.},
  language  = {en}
}
@inproceedings{SteenholdtEdlundAinsworthetal.2015,
  author    = {Steenholdt, Casper and Edlund, Helena and Ainsworth, Mark A. and Brynskov, Jorn and Thomsen, Ole Ostergaard and Huisinga, Wilhelm and Kloft, Charlotte},
  title     = {Relationship between measures of infliximab exposure and clinical outcome of infliximab intensification at therapeutic failure in Crohn's disease},
  series = {JOURNAL OF CROHNS \& COLITIS},
  volume    = {9},
  booktitle = {JOURNAL OF CROHNS \& COLITIS},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {1873-9946},
  pages     = {S330 -- S330},
  year      = {2015},
  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}
}