TY - CHAP A1 - Andersson, H. A1 - Keunecke, A. A1 - Eser, A. A1 - Huisinga, Wilhelm A1 - Reinisch, W. A1 - Kloft, Charlotte T1 - Pharmacokinetic considerations for optimising dosing regimens of a potsdam univ infliximab in patients with Crohn's disease T2 - JOURNAL OF CROHNS & COLITIS Y1 - 2014 U6 - https://doi.org/10.1016/S1873-9946(14)60086-6 SN - 1873-9946 SN - 1876-4479 VL - 8 SP - S44 EP - S44 PB - Oxford Univ. Press CY - Oxford ER - TY - CHAP A1 - Démaris, Alise A1 - Grišić, Ana-Marija A1 - Huisinga, Wilhelm A1 - Walter, Reinisch A1 - Kloft, Charlotte T1 - Evaluation of dosing strategies of anti-TNF alpha monoclonal antibodies using pharmacokinetic modelling and simulation T2 - Journal of Crohn's and Colitis N2 - 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). KW - linical databases KW - crohn's disease KW - regimen KW - monoclonal antibodies KW - body surface area KW - infliximab KW - fat-free mass KW - certolizumab pegol KW - body mass index procedure Y1 - 2020 U6 - https://doi.org/10.1093/ecco-jcc/jjz203.201 SN - 1873-9946 SN - 1876-4479 VL - 14 IS - Supp. 1 SP - S171 EP - S172 PB - Oxford Univ. Press CY - Oxford ER - TY - JOUR A1 - Démaris, Alix A1 - Widigson, Ella S. K. A1 - Ilvemark, Johan F. K. F. A1 - Steenholdt, Casper A1 - Seidelin, Jakob B. A1 - Huisinga, Wilhelm A1 - Michelet, Robin A1 - Aulin, Linda B. S. A1 - Kloft, Charlotte T1 - Ulcerative colitis and acute severe ulcerative colitis patients are overlooked in infliximab population pharmacokinetic models BT - results from a comprehensive review JF - Pharmaceutics / Molecular Diversity Preservation International N2 - Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis alpha monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting. KW - infliximab KW - inflammatory bowel disease KW - ulcerative colitis KW - acute severe KW - disease activity KW - pharmacokinetic KW - pharmacometrics Y1 - 2022 U6 - https://doi.org/10.3390/pharmaceutics14102095 SN - 1999-4923 VL - 14 IS - 10 PB - MDPI CY - Basel 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 - Ehmann, Lisa A1 - Zoller, Michael A1 - Minichmayr, Iris K. A1 - Scharf, Christina A1 - Huisinga, Wilhelm A1 - Zander, Johannes A1 - Kloft, Charlotte T1 - Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis JF - International journal of antimicrobial agents N2 - 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. KW - beta-Lactams KW - Intensive care KW - Pharmacokinetics/pharmacodynamics KW - Renal function KW - Dosing algorithm Y1 - 2019 U6 - https://doi.org/10.1016/j.ijantimicag.2019.06.016 SN - 0924-8579 SN - 1872-7913 VL - 54 IS - 3 SP - 309 EP - 317 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Ehmann, Lisa A1 - Zoller, Michael A1 - Minichmayr, Iris K. A1 - Scharf, Christina A1 - Maier, Barbara A1 - Schmitt, Maximilian V. A1 - Hartung, Niklas A1 - Huisinga, Wilhelm A1 - Vogeser, Michael A1 - Frey, Lorenz A1 - Zander, Johannes A1 - Kloft, Charlotte T1 - Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients BT - a prospective observational study JF - Critical care N2 - 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. KW - beta-Lactam KW - Intensive care KW - Pharmacokinetics/Pharmacodynamics KW - Target attainment KW - Renal function KW - Risk assessment tool KW - Continuous renal replacement therapy Y1 - 2017 U6 - https://doi.org/10.1186/s13054-017-1829-4 SN - 1466-609X SN - 1364-8535 VL - 21 PB - BioMed Central CY - London ER - TY - GEN A1 - Ehmann, Lisa A1 - Zoller, Michael A1 - Minichmayr, Iris K. A1 - Schmitt, Maximilian V. A1 - Hartung, Niklas A1 - Huisinga, Wilhelm A1 - Zander, Johannes A1 - Kloft, Charlotte T1 - Development of a tool to identify intensive care patients at risk of meropenem therapy failure T2 - International Journal of Clinical Pharmacy Y1 - 2018 SN - 2210-7703 SN - 2210-7711 VL - 40 IS - 1 SP - 317 EP - 317 PB - Springer CY - Dordrecht ER - TY - JOUR A1 - Fronton, Ludivine A1 - Pilari, Sabine A1 - Huisinga, Wilhelm T1 - Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models JF - Journal of pharmacokinetics and pharmacodynamics N2 - The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two-compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice. KW - mAb disposition KW - PBPK KW - Extravasation rate-limited tissue model KW - Classical compartment model Y1 - 2014 U6 - https://doi.org/10.1007/s10928-014-9349-1 SN - 1567-567X SN - 1573-8744 VL - 41 IS - 2 SP - 87 EP - 107 PB - Springer CY - New York ER - TY - JOUR A1 - Fuhrmann, Saskia A1 - Kloft, Charlotte A1 - Huisinga, Wilhelm T1 - Impact of altered endogenous IgG on unspecific mAb clearance JF - Journal of pharmacokinetics and pharmacodynamics N2 - 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. KW - mAb disposition KW - PBPK KW - FcRn salvage mechanism KW - Immunodeficient mice models KW - Unspecific antibody clearance Y1 - 2017 U6 - https://doi.org/10.1007/s10928-017-9524-2 SN - 1567-567X SN - 1573-8744 VL - 44 SP - 351 EP - 374 PB - Springer CY - New York ER - TY - JOUR A1 - Gopalakrishnan, Sathej A1 - Montazeri, Hesam A1 - Menz, Stephan A1 - Beerenwinkel, Niko A1 - Huisinga, Wilhelm T1 - Estimating HIV-1 fitness characteristics from cross-sectional genotype data JF - PLoS Computational Biology : a new community journal N2 - Despite the success of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV)-1 infection, virological failure due to drug resistance development remains a major challenge. Resistant mutants display reduced drug susceptibilities, but in the absence of drug, they generally have a lower fitness than the wild type, owing to a mutation-incurred cost. The interaction between these fitness costs and drug resistance dictates the appearance of mutants and influences viral suppression and therapeutic success. Assessing in vivo viral fitness is a challenging task and yet one that has significant clinical relevance. Here, we present a new computational modelling approach for estimating viral fitness that relies on common sparse cross-sectional clinical data by combining statistical approaches to learn drug-specific mutational pathways and resistance factors with viral dynamics models to represent the host-virus interaction and actions of drug mechanistically. We estimate in vivo fitness characteristics of mutant genotypes for two antiretroviral drugs, the reverse transcriptase inhibitor zidovudine (ZDV) and the protease inhibitor indinavir (IDV). Well-known features of HIV-1 fitness landscapes are recovered, both in the absence and presence of drugs. We quantify the complex interplay between fitness costs and resistance by computing selective advantages for different mutants. Our approach extends naturally to multiple drugs and we illustrate this by simulating a dual therapy with ZDV and IDV to assess therapy failure. The combined statistical and dynamical modelling approach may help in dissecting the effects of fitness costs and resistance with the ultimate aim of assisting the choice of salvage therapies after treatment failure. Y1 - 2014 U6 - https://doi.org/10.1371/journal.pcbi.1003886 SN - 1553-734X SN - 1553-7358 VL - 10 IS - 11 PB - PLoS CY - San Fransisco ER -