TY - JOUR
A1 - Mueller-Schoell, Anna
A1 - Groenland, Stefanie L.
A1 - Scherf-Clavel, Oliver
A1 - van Dyk, Madele
A1 - Huisinga, Wilhelm
A1 - Michelet, Robin
A1 - Jaehde, Ulrich
A1 - Steeghs, Neeltje
A1 - Huitema, Alwin D. R.
A1 - Kloft, Charlotte
T1 - Therapeutic drug monitoring of oral targeted antineoplastic drugs
JF - European journal of clinical pharmacology
N2 - Purpose This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. Methods A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. Results OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. Conclusion Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.
KW - targeted antineoplastic drugs
KW - tyrosine kinase inhibitors
KW - therapeutic
KW - drug monitoring
KW - oral anticancer drugs
KW - personalised medicine
Y1 - 2020
U6 - https://doi.org/10.1007/s00228-020-03014-8
SN - 0031-6970
SN - 1432-1041
VL - 77
IS - 4
SP - 441
EP - 464
PB - Springer
CY - Heidelberg
ER -
TY - JOUR
A1 - Grisic, Ana-Marija
A1 - Eser, Alexander
A1 - Huisinga, Wilhelm
A1 - Reinisch, Walter
A1 - Kloft, Charlotte
T1 - Quantitative relationship between infliximab exposure and inhibition of C-reactive protein synthesis to support inflammatory bowel disease management
JF - British journal of clinical pharmacology
N2 - 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.
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.
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.
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.
KW - C‐ reactive protein remission
KW - inflammatory bowel disease
KW - infliximab dosing
Y1 - 2020
U6 - https://doi.org/10.1111/bcp.14648
SN - 0306-5251
SN - 1365-2125
VL - 87
IS - 5
SP - 2374
EP - 2384
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Kluwe, Franziska
A1 - Michelet, Robin
A1 - Müller-Schöll, Anna
A1 - Maier, Corinna
A1 - Klopp-Schulze, Lena
A1 - van Dyk, Madele
A1 - Mikus, Gerd
A1 - Huisinga, Wilhelm
A1 - Kloft, Charlotte
T1 - Perspectives on model-informed precision dosing in the digital health era
BT - challenges, opportunities, and recommendations
JF - Clinical pharmacology & therapeutics
Y1 - 2020
U6 - https://doi.org/10.1002/cpt.2049
SN - 0009-9236
SN - 1532-6535
VL - 109
IS - 1
SP - 29
EP - 36
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Nassar, Yomna M.
A1 - Hohmann, Nicolas
A1 - Michelet, Robin
A1 - Gottwalt, Katharina
A1 - Meid, Andreas D.
A1 - Burhenne, Jürgen
A1 - Huisinga, Wilhelm
A1 - Haefeli, Walter E.
A1 - Mikus, Gerd
A1 - Kloft, Charlotte
T1 - Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion
JF - Clinical Pharmacokinetics
N2 - 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.
Y1 - 2022
U6 - https://doi.org/10.1007/s40262-022-01175-6
SN - 0312-5963
SN - 1179-1926
VL - 61
IS - 11
SP - 1595
EP - 1607
PB - Springer
CY - Northcote
ER -
TY - GEN
A1 - Grisic, Ana-Marija
A1 - Huisinga, Wilhelm
A1 - Reinisch, W.
A1 - Kloft, Charlotte
T1 - P485 Dosing infliximab in Crohn's disease
BT - is adjustment for body size justified?
T2 - Journal of Crohn's and Colitis
N2 - 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.
Y1 - 2017
U6 - https://doi.org/10.1093/ecco-jcc/jjx002.609
SN - 1873-9946
SN - 1876-4479
VL - 11
IS - 1
SP - S325
EP - S326
PB - Oxford Univ. Press
CY - Oxford
ER -
TY - GEN
A1 - Weisser, Karin
A1 - Stübler, Sabine
A1 - Matheis, Walter
A1 - Huisinga, Wilhelm
T1 - Towards toxicokinetic modelling of aluminium exposure from adjuvants in medicinal products
T2 - Regulatory toxicology and pharmacology : official journal of the International Society for Regulatory Toxicology and Pharmacology
N2 - As a potentially toxic agent on nervous system and bone, the safety of aluminium exposure from adjuvants in vaccines and subcutaneous immune therapy (SCIT) products has to be continuously reevaluated, especially regarding concomitant administrations. For this purpose, knowledge on absorption and disposition of aluminium in plasma and tissues is essential. Pharmacokinetic data after vaccination in humans, however, are not available, and for methodological and ethical reasons difficult to obtain. To overcome these limitations, we discuss the possibility of an in vitro-in silico approach combining a toxicokinetic model for aluminium disposition with biorelevant kinetic absorption parameters from adjuvants. We critically review available kinetic aluminium-26 data for model building and, on the basis of a reparameterized toxicokinetic model (Nolte et al., 2001), we identify main modelling gaps. The potential of in vitro dissolution experiments for the prediction of intramuscular absorption kinetics of aluminium after vaccination is explored. It becomes apparent that there is need for detailed in vitro dissolution and in vivo absorption data to establish an in vitro-in vivo correlation (IVIVC) for aluminium adjuvants. We conclude that a combination of new experimental data and further refinement of the Nolte model has the potential to fill a gap in aluminium risk assessment. (C) 2017 Elsevier Inc. All rights reserved.
KW - Aluminium
KW - Aluminium adjuvants
KW - Absorption kinetics
KW - Toxicokinetic modelling
KW - In vitro dissolution
Y1 - 2017
U6 - https://doi.org/10.1016/j.yrtph.2017.02.018
SN - 0273-2300
SN - 1096-0295
VL - 88
SP - 310
EP - 321
PB - Elsevier
CY - San Diego
ER -
TY - JOUR
A1 - Wicha, Sebastian G.
A1 - Huisinga, Wilhelm
A1 - Kloft, Charlotte
T1 - Translational pharmacometric evaluation of typical antibiotic broad-spectrum combination therapies against staphylococcus aureus exploiting in vitro information
JF - CPT: pharmacometrics & systems pharmacology
N2 - Broad-spectrum antibiotic combination therapy is frequently applied due to increasing resistance development of infective pathogens. The objective of the present study was to evaluate two common empiric broad-spectrum combination therapies consisting of either linezolid (LZD) or vancomycin (VAN) combined with meropenem (MER) against Staphylococcus aureus (S. aureus) as the most frequent causative pathogen of severe infections. A semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) model mimicking a simplified bacterial life-cycle of S. aureus was developed upon time-kill curve data to describe the effects of LZD, VAN, and MER alone and in dual combinations. The PK-PD model was successfully (i) evaluated with external data from two clinical S. aureus isolates and further drug combinations and (ii) challenged to predict common clinical PK-PD indices and breakpoints. Finally, clinical trial simulations were performed that revealed that the combination of VAN-MER might be favorable over LZD-MER due to an unfavorable antagonistic interaction between LZD and MER.
Y1 - 2017
U6 - https://doi.org/10.1002/psp4.12197
SN - 2163-8306
VL - 6
SP - 512
EP - 522
PB - Wiley
CY - Hoboken
ER -
TY - JOUR
A1 - Edlund, Helena
A1 - Grisic, Ana-Marija
A1 - Steenholdt, Casper
A1 - Ainsworth, Mark Andrew
A1 - Brynskov, Torn
A1 - Huisinga, Wilhelm
A1 - Kloft, Charlotte
T1 - 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
JF - Therapeutic drug monitoring : official journal of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology
N2 - 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.
Y1 - 2019
U6 - https://doi.org/10.1097/FTD.0000000000000590
SN - 0163-4356
SN - 1536-3694
VL - 41
IS - 2
SP - 235
EP - 242
PB - Lippincott Williams & Wilkins
CY - Philadelphia
ER -
TY - JOUR
A1 - Knöchel, Jane
A1 - Kloft, Charlotte
A1 - Huisinga, Wilhelm
T1 - Understanding and reducing complex systems pharmacology models based on a novel input-response index
JF - Journal of pharmacokinetics and pharmacodynamics
N2 - A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input–response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input–output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable. In this article, we present a novel state- and time-dependent quantity called the input–response index that quantifies the importance of state variables for a given input–response relationship at a particular time. It is based on the concept of time-bounded controllability and observability, and defined with respect to a reference dynamics. In application to the brown snake venom–fibrinogen (Fg) network, the input–response indices give insight into the coordinated action of specific coagulation factors and about those factors that contribute only little to the response. We demonstrate how the indices can be used to reduce large-scale models in a two-step procedure: (i) elimination of states whose dynamics have only minor impact on the input–response relationship, and (ii) proper lumping of the remaining (lower order) model. In application to the brown snake venom–fibrinogen network, this resulted in a reduction from 62 to 8 state variables in the first step, and a further reduction to 5 state variables in the second step. We further illustrate that the sequence, in which a recursive algorithm eliminates and/or lumps state variables, has an impact on the final reduced model. The input–response indices are particularly suited to determine an informed sequence, since they are based on the dynamics of the original system. In summary, the novel measure of importance provides a powerful tool for analysing the complex dynamics of large-scale systems and a means for very efficient model order reduction of nonlinear systems.
KW - Control theory
KW - Model order reduction
KW - Blood coagulation network
KW - Nonlinear systems
Y1 - 2017
U6 - https://doi.org/10.1007/s10928-017-9561-x
SN - 1567-567X
SN - 1573-8744
VL - 45
IS - 1
SP - 139
EP - 157
PB - Springer Science + Business Media B.V.
CY - New York
ER -
TY - THES
A1 - Knöchel, Jane
T1 - Model reduction of mechanism-based pharmacodynamic models and its link to classical drug effect models
T1 - Modellreduktion von mechanistischen pharmacodynamischen Modellen und deren Verbindung zu klassischen Wirkstoff-Effekt-Modellen
N2 - Continuous insight into biological processes has led to the development of large-scale, mechanistic systems biology models of pharmacologically relevant networks. While these models are typically designed to study the impact of diverse stimuli or perturbations on multiple system variables, the focus in pharmacological research is often on a specific input, e.g., the dose of a drug, and a specific output related to the drug effect or response in terms of some surrogate marker.
To study a chosen input-output pair, the complexity of the interactions as well as the size of the models hinders easy access and understanding of the details of the input-output relationship.
The objective of this thesis is the development of a mathematical approach, in specific a model reduction technique, that allows (i) to quantify the importance of the different state variables for a given input-output relationship, and (ii) to reduce the dynamics to its essential features -- allowing for a physiological interpretation of state variables as well as parameter estimation in the statistical analysis of clinical data. We develop a model reduction technique using a control theoretic setting by first defining a novel type of time-limited controllability and observability gramians for nonlinear systems. We then show the superiority of the time-limited generalised gramians for nonlinear systems in the context of balanced truncation for a benchmark system from control theory.
The concept of time-limited controllability and observability gramians is subsequently used to introduce a state and time-dependent quantity called the input-response (ir) index that quantifies the importance of state variables for a given input-response relationship at a particular time.
We subsequently link our approach to sensitivity analysis, thus, enabling for the first time the use of sensitivity coefficients for state space reduction. The sensitivity based ir-indices are given as a product of two sensitivity coefficients. This allows not only for a computational more efficient calculation but also for a clear distinction of the extent to which the input impacts a state variable and the extent to which a state variable impacts the output.
The ir-indices give insight into the coordinated action of specific state variables for a chosen input-response relationship.
Our developed model reduction technique results in reduced models that still allow for a mechanistic interpretation in terms of the quantities/state variables of the original system, which is a key requirement in the field of systems pharmacology and systems biology and distinguished the reduced models from so-called empirical drug effect models. The ir-indices are explicitly defined with respect to a reference trajectory and thereby dependent on the initial state (this is an important feature of the measure). This is demonstrated for an example from the field of systems pharmacology, showing that the reduced models are very informative in their ability to detect (genetic) deficiencies in certain physiological entities. Comparing our novel model reduction technique to the already existing techniques shows its superiority.
The novel input-response index as a measure of the importance of state variables provides a powerful tool for understanding the complex dynamics of large-scale systems in the context of a specific drug-response relationship. Furthermore, the indices provide a means for a very efficient model order reduction and, thus, an important step towards translating insight from biological processes incorporated in detailed systems pharmacology models into the population analysis of clinical data.
N2 - Die kontinuierliche Erforschung von biologischen Prozessen hat zur Entwicklung umfangreicher, mechanistischer systembiologischer Modelle von pharmakologisch relevanten Netzwerken beigetragen. Während diese Modelle in der Regel darauf ausgelegt sind, die Auswirkung von Stimuli oder Störungen auf die Systemdynamik zu untersuchen, liegt der Fokus in der pharmakologis- chen Forschung häufig auf einer bestimmten Kontrolle, z.B. der Dosis eines Wirkstoffes, und einer bestimmten Ausgangsgröße, welche in Bezug steht zu dem Wirkstoff-Effekt oder das Ansprechen auf einen Wirkstoff über einen Surrogatmarker. Die Untersuchung und ein einfaches Verständnis einer spezifischen Eingabe-Ausgabe-Beziehung wird durch die Komplexität der Interaktionen sowie der Größe des Modells erschwert.
Das Ziel dieser vorliegenden Arbeit ist die Entwicklung eines mathematischen Ansatzes, insbesondere eines Modellreduktionsverfahrens, der es ermöglicht, (i) die Bedeutung der verschiedenen Zustandsvariablen für eine gegebene Eingabe-Ausgabe-Beziehung zu quantifizieren, und (ii) die Dynamik des Systems auf seine wesentlichen Merkmale zu reduzieren, während gleichzeitig die physiologische Interpretierbarkeit von Zustandsvariablen sowie eine Parameterschätzung im Rahmen von einer statistischen Analyse klinischer Daten ermöglicht wird. Unter Verwendung eines kontrolltheoretischen Settings entwickeln wir eine Modellreduktionstechnik, indem wir vorerst einen neuartigen Typ von zeitlich begrenzten Kontrolllierbarkeits- und Beobachtbarkeitsgramian für nichtlineare Systeme definieren. Anschließend zeigen wir die Überlegenkeit der zeitlich begrenzten verallgemeinerten Gramian für nichtlineare Systeme im Kontext von Balanced Truncation am Beispiel eines Benchmark-Systems aus der Kontrolltheorie. Wir nutzten das Konzept der zeitlich begrenzten Kontrolllierbarkeits- und Beobachtbarkeitsgramian, um eine neue Zustands- und zeitabhängige Größe, die als Input-Response (IR-) Index bezeichnet wird, einzuführen. Dieser Index quantifiziert die Bedeutung von Zustandsvariablen zu einem bestimmten Zeitpunkt für eine bestimmte Eingabe-Ausgabe-Beziehung. Schließlich verknüpfen wir unseren Ansatz mit der Sensitivitätsanalyse und ermöglichen so erstmals die Verwendung von Sensitivitätskoeffizienten im Rahmen der Reduktion des Zustandsraumes. Wir erhalten die sensitivitätsbasierten IR-Indizes als Produkt zweier Sensitivitätskoeffizienten. Dies ermöglicht nicht nur eine effizientere Berechnung, sondern auch eine klare Unterscheidung, inwieweit die Eingabe eine Zustandsvariable beeinflusst und inwieweit eine Zustandsvariable die Ausgabe beeinflusst. Mit Hilfe der IR-Indizes erhalten wir einen Einblick in den koordinierten Ablauf der Aktivierung von spezifischen Zustandsvariablen für eine ausgewählte Eingabe-Ausgabe-Beziehung. Unser entwickeltes Modellreduktionsverfahren resultiert in reduzierten Modelle, welche eine mechanistische Interpretation hinsichtlich der Originalgrößen und Zustandsvariablen des Ursprungssystems zulassen. Dies war eine wichtige Anforderung an das Verfahren von Seiten der Systempharmakologie und -biologie. Die reduzierten Modelle unterscheiden sich damit wesentlich von den so genannten empirischen Wirkstoff-Effekt-Modellen. Die IR-Indizes sind explizit in Bezug auf eine Referenzlösung definiert und damit vom Anfangszustand abhängig (dies ist ein wichtiges Merkmal der Indizes). Wir zeigen anhand eines Beispiels aus dem Bereich der Systempharmakologie, dass die reduzierten Modelle sehr aussagekräftig sind, um (genetische) Mängel in bestimmten physiologischen Einheiten festzustellen. Der Vergleich unseres neuartigen Modellreduktionsverfahrens mit den bereits vorhandenen Verfahren zeigt dessen Überlegenheit.
Der neuartige IR-Index als Maß für die Wichtigkeit von Zustandsvariablen bietet ein leistungsfähiges mathematisches Werkzeug zum Verständnis und der Analyse der komplexen Dynamik von großen Systemen im Kontext einer bestimmten Wirkstoff-Effekt-Beziehung. Darüber hinaus sind die Indizes eine wichtige Grundlage für das eingeführte und sehr effiziente Modellreduktionsverfahren. Insgesamt stellt dies einen wichtigen Schritt zur Nutzung von Erkenntnissen über biologische Prozesse in Form von detaillierten systempharmakologischen Modellen in der Populationsanalyse klinischer Daten dar.
KW - model order reduction
KW - control theory
KW - large-scale mechanistic systems
KW - systems pharmacology
KW - Modellreduktion
KW - Kontrolltheorie
KW - komplexe mechanistische Systeme
KW - Systempharmakologie
Y1 - 2019
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-440598
ER -