24 results on '"Friberg, Lena E."'
Search Results
2. In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections
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Nutman, Amir Temkin, Elizabeth Lellouche, Jonathan and Rakovitsky, Nadya Hameir, Amichay Daikos, George and Durante-Mangoni, Emanuele Pavleas, Ioannis Dishon, Yael and Petersiel, Neta Yahav, Dafna Eliakim, Noa Bernardo, Mariano and Iossa, Domenico Friberg, Lena E. Theuretzbacher, Ursula and Leibovici, Leonard Paul, Mical Carmeli, Yehuda AIDA Study Grp
- Abstract
Objectives: Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections. Methods: Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 105 CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes. Results: The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04-2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03-2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95-2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09-3.25). Conclusions: In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection. Amir Nutman, Clin Microbiol Infect 2022;28:73 (c) 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
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- 2022
3. Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance
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Frenk, Sammy Temkin, Elizabeth Lurie-Weinberger, Mor N. Keren-Paz, Alona Rov, Reut Rakovitsky, Nadya Wullfhart, Liat Nutman, Amir Daikos, George L. Skiada, Anna Durante-Mangoni, Emanuele Dishon Benattar, Yael Bitterman, Roni Yahav, Dafna Daitch, Vered Bernardo, Mariano Iossa, Domenico Zusman, Oren Friberg, Lena E. Mouton, Johan W. Theuretzbacher, Ursula Leibovici, Leonard Geffen, Yuval Gershon, Rina Paul, Mical Carmeli, Yehuda
- Abstract
OBJECTIVES: To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries. METHODS: Isolates were collected during the 2013-17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed. RESULTS: In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily blaOXA-23. The chromosomal oxaAb (blaOXA-51-like) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1α. CONCLUSIONS: The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade’s/ST’s success.
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- 2022
4. Comparing Circulating Tumor Cell Counts with Dynamic Tumor Size Changes as Predictor of Overall Survival: A Quantitative Modeling Framework: A Quantitative Modeling Framework
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Netterberg, Ida, Karlsson, Mats O., Terstappen, Leon W. M. M., Koopman, Miriam, Punt, Cornelis J. A., Friberg, Lena E., Oncology, and CCA - Imaging and biomarkers
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digestive system diseases - Abstract
Purpose: Quantitative relationships between treatment-induced changes in tumor size and circulating tumor cell (CTC) counts, and their links to overall survival (OS), are lacking. We present a population modeling framework identifying and quantifying such relationships, based on longitudinal data collected in patients with metastatic colorectal cancer (mCRC) to evaluate the value of tumor size and CTC counts as predictors of OS. Experimental Design: A pharmacometric approach (i.e., population pharmacodynamic modeling) was used to characterize the changes in tumor size and CTC count and evaluate them as predictors of OS in 451 patients with mCRC treated with chemotherapy and targeted therapy in a prospectively randomized phase III study (CAIRO2). Results: A tumor size model of tumor quiescence and drug resistance was used to characterize the tumor size time-course, and was, in addition to the total normalized dose (i.e., of all administered drugs) in a given cycle, related to the CTC counts through a negative binomial model (CTC model). Tumor size changes did not contribute additional predictive value when the mean CTC count was a predictor of OS. Treatment reduced the typical mean count from 1.43 to 0.477 (HR ¼ 3.94). The modeling framework was applied to explore whether dose modifications (increased and reduced) would result in a CTC count below 1/7.5 mL after 1 to 2 weeks of treatment. Conclusions: Time-varying CTC counts can be useful for early predicting OS in patients with mCRC, and may therefore have potential for model-based treatment individualization. Although tumor size was connected to CTC, its link to OS was weaker.
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- 2020
5. Considerations for the optimal management of antibiotic therapy in elderly patients
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Falcone, Marco, Paul, Mical, Tiseo, Giusy, Yahav, Dafna, Prendki, Virginie, Friberg, Lena E., Guerri, Roberto, Gavazzi, Gaetan, Mussini, Cristina, Tinelli, Marco, and ESCMID Study Group for Infections in the Elderly (ESGIE)
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Dosage ,Elderly ,Pharmacodynamics ,Antibiotics ,health care facilities, manpower, and services ,Adverse events ,ddc:618.97 ,Pharmacokinetics ,social sciences ,humanities - Abstract
Objectives: To maximise efficacy and minimise toxicity, special considerations are required for antibiotic prescription in elderly patients. This review aims to provide practical suggestions for the optimal management of antibiotic therapy in elderly patients.
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- 2020
6. Combination of polymyxin B and minocycline against multidrug-resistant Klebsiella pneumoniae : interaction quantified by pharmacokinetic/pharmacodynamic modelling from in vitro data
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Zhao, Chenyan, Wistrand-Yuen, Pikkei, Lagerbäck, Pernilla, Tängdén, Thomas, Nielsen, Elisabet I., and Friberg, Lena E.
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Pharmaceutical Sciences ,Pharmacokinetic ,Minocycline ,Pharmacology and Toxicology ,Combination therapy ,Farmaceutiska vetenskaper ,Farmakologi och toxikologi ,In vitro time-kill study ,pharmacodynamic model ,Multidrug-resistant Klebsiella pneumoniae ,Polymyxin B - Abstract
Lack of effective treatment for multidrug-resistant Klebsiella pneumoniae (MDR-Kp) necessitates finding and optimising combination therapies of old antibiotics. The aims of this study were to quantify the combined effect of polymyxin B and minocycline by building an in silico semi-mechanistic pharmacokinetic/pharmacodynamic (PKPD) model and to predict bacterial kinetics when exposed to the drugs alone and in combination at clinically achievable unbound drug concentration-time profiles. A clinical K. pneumoniae strain resistant to polymyxin B [minimum inhibitory concentration (MIC) = 16 mg/L] and minocycline (MIC = 16 mg/L) was selected for extensive in vitro static time-kill experiments. The strain was exposed to concentrations of 0.0625-48 ? MIC, with seven samples taken per experiment for viable counts during 0-28 h. These observations allowed the development of the PKPD model. The final PKPD model included drug-induced adaptive resistance for both drugs. Both the minocycline-induced bacterial killing and resistance onset rate constants were increased when polymyxin B was co-administered, whereas polymyxin B parameters were unaffected. Predictions at clinically used dosages from the developed PKPD model showed no or limited antibacterial effect with monotherapy, whilst combination therapy kept bacteria below the starting inoculum for 20 h at high dosages [polymyxin B 2.5 mg/kg + 1.5 mg/kg every 12 h (q12h); minocycline 400 mg + 200 mg q12h, loading + maintenance doses]. This study suggests that polymyxin B and minocycline in combination may be of clinical benefit in the treatment of infections by MDR-Kp and for isolates that are non-susceptible to either drug alone. (C) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
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- 2020
7. A Pharmacometric Framework for Axitinib Exposure, Efficacy, and Safety in Metastatic Renal Cell Carcinoma Patients
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Schindler, Emilie, Amantea, Michael A, Karlsson, Mats O, and Friberg, Lena E
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Vascular Endothelial Growth Factor A ,Indazoles ,Vascular Endothelial Growth Factor Receptor-1 ,Axitinib ,Imidazoles ,Antineoplastic Agents ,Blood Pressure ,Original Articles ,Kaplan-Meier Estimate ,Farmaceutiska vetenskaper ,Vascular Endothelial Growth Factor Receptor-3 ,Models, Biological ,Vascular Endothelial Growth Factor Receptor-2 ,Kidney Neoplasms ,Tumor Burden ,Pharmaceutical Sciences ,Proto-Oncogene Proteins c-kit ,Treatment Outcome ,Biomarkers, Tumor ,Humans ,Original Article ,Carcinoma, Renal Cell ,Protein Kinase Inhibitors - Abstract
The relationships between exposure, biomarkers (vascular endothelial growth factor (VEGF), soluble VEGF receptors (sVEGFR)-1, -2, -3, and soluble stem cell factor receptor (sKIT)), tumor sum of longest diameters (SLD), diastolic blood pressure (dBP), and overall survival (OS) were investigated in a modeling framework. The dataset included 64 metastatic renal cell carcinoma patients (mRCC) treated with oral axitinib. Biomarker timecourses were described by indirect response (IDR) models where axitinib inhibits sVEGFR-1, -2, and -3 production, and VEGF degradation. No effect was identified on sKIT. A tumor model using sVEGFR-3 dynamics as driver predicted SLD data well. An IDR model, with axitinib exposure stimulating the response, characterized dBP increase. In a time-to-event model the SLD timecourse predicted OS better than exposure, biomarker- or dBP-related metrics. This type of framework can be used to relate pharmacokinetics, efficacy, and safety to long-term clinical outcome in mRCC patients treated with VEGFR inhibitors. (ClinicalTrial.gov identifier NCT00569946.).
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- 2017
8. Erratum to: Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen
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Thorsted, Anders, Kristoffersson, Anders N, Maarbjerg, Sabine F, Schrøder, Henrik, Wang, Mikala, Brock, Birgitte, Nielsen, Elisabet I, and Friberg, Lena E
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Pharmacology ,Microbiology (medical) ,Infectious Diseases ,Pharmacology (medical) ,Original Research - Abstract
Background The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target. Objectives To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights. Methods Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. Results A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4 L/h (70 kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT > 4×MIC was achieved for an MIC of 4.0 mg/L in a typical patient with extended infusions of 2–3 (q6h) or 3–4 (q8h) h, at or below the standard adult dose (75 and 100 mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT > 1×MIC due to the rapid piperacillin elimination. Conclusions The licensed dose for children with febrile neutropenia (80 mg/kg q6h as a 30 min infusion) performs poorly for attainment of fT>MIC pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT > 1×MIC) or prolonged infusions (50% fT > 4×MIC).
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- 2019
9. A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6
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Thorsted, Anders, Bouchene, Salim, Tano, Eva, Castegren, Markus, Lipcsey, Miklós, Sjölin, Jan, Karlsson, Mats O., Friberg, Lena E., and Nielsen, Elisabet I.
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Fysiologi ,Physiology ,Swine ,Toxicology ,Pathology and Laboratory Medicine ,Pig Models ,Antibiotics ,Immune Physiology ,Medicine and Health Sciences ,Toxins ,Infusions, Intravenous ,Immune Response ,Innate Immune System ,Antimicrobials ,Simulation and Modeling ,Drugs ,Animal Models ,Experimental Organism Systems ,Medicine ,Cytokines ,Research Article ,Science ,Immunology ,Toxic Agents ,Bacterial Toxins ,Research and Analysis Methods ,Microbiology ,Signs and Symptoms ,Spatio-Temporal Analysis ,Diagnostic Medicine ,Microbial Control ,Sepsis ,Escherichia coli ,Animals ,Computer Simulation ,Pharmacology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Biology and Life Sciences ,Molecular Development ,Endotoxemia ,Immunity, Innate ,Endotoxins ,Disease Models, Animal ,Nonlinear Dynamics ,Immune System ,Animal Studies ,Developmental Biology - Abstract
Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and associated tolerance development. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111: B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 mu g/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-alpha to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-alpha concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-alpha production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-a, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-alpha and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.
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- 2019
10. Model-Based Drug Development in Pulmonary Delivery : Pharmacokinetic Analysis of Novel Drug Candidates for Treatment of Pseudomonas aeruginosa Lung Infection
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Sou, Tomás, Kukavica-Ibrulj, Irena, Soukarieh, Fadi, Halliday, Nigel, Levesque, Roger C., Williams, Paul, Stocks, Michael, Camara, Miguel, Friberg, Lena E., and Bergström, Christel A. S.
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solubility ,Pharmacology and Toxicology ,Farmakologi och toxikologi ,Farmaceutiska vetenskaper ,metabolic clearance ,Pharmaceutical Sciences ,disposition ,preclinical pharmacokinetics ,distribution ,PK/PD modeling ,simulations ,pulmonary drug delivery ,absorption ,pharmacometrics - Abstract
Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of antivirulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitize PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of 3 prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a pharmacometric modeling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results show that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we suggest that novel QSIs designed for pulmonary delivery as targeted treatments for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of systemic adverse events.
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- 2019
11. Model-based drug development in pulmonary delivery: pharmacokinetic analysis of novel drug candidates for treatment of Pseudomonas aeruginosa lung infection
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Kukavica-Ibrulj, Irena, Soukarieh, Fadi, Halliday, Nigel, Levesque, Roger C., Williams, Paul, Stocks, Michael, and Friberg, Lena E.
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solubility ,disposition ,distribution ,PK/PD modeling ,simulations ,pulmonary drug delivery ,preclinical pharmacokineticsabsorption ,pharmacometrics ,metabolic clearance - Abstract
Antibiotic resistance is a major public health threat worldwide. In particular, about 80% of cystic fibrosis patients have chronic Pseudomonas aeruginosa (PA) lung infection resistant to many current antibiotics. We are therefore developing a novel class of anti-virulence agents, quorum sensing inhibitors (QSIs), which inhibit biofilm formation and sensitise PA to antibiotic treatments. For respiratory conditions, targeted delivery to the lung could achieve higher local concentrations with reduced risk of adverse systemic events. In this study, we report the pharmacokinetics of three prototype QSIs after pulmonary delivery, and the simultaneous analysis of the drug concentration-time profiles from bronchoalveolar lavage, lung homogenate and plasma samples, using a modelling approach. In addition to facilitating the direct comparison and selection of drug candidates, the developed model was used for dosing simulation studies to predict in vivo exposure following different dosing scenarios. The results suggest that systemic clearance has limited impact on local drug exposure in the lung after pulmonary delivery. Therefore, we believe that novel QSIs designed for pulmonary delivery as targeted treatment for respiratory conditions should ideally have a long residence time in the lung for local efficacy with rapid clearance after systemic absorption for reduced risk of adverse systemic events.
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- 2019
12. A Pharmacokinetic-Pharmacodynamic model built on in vitro data predicts the antibacterial effect of polymyxin B against Klebsiella pneumoniae in vivo
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Zhigang Wang, Chenyan Zhao, Berg, Sanne Van Den, Mouton, Johan, Nielsen, Elisabet I, and Friberg, Lena E
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- 2019
- Full Text
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13. Optimization of Piperacillin-Tazobactam Treatment in Pediatric Oncology Patients with Fever - a Prospective Study':Presented as an oral presentation at the NOPHO 36th Annual Meeting | NOBOS 12th Biannual Meeting in Vilnius, Lithuania on 1-6 June, 2018 on Sunday 03-06 at 15:45-16:00
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Maarbjerg, Sabine Frølich, Thorsted, Anders, Kristoffersson, Anders N, Friberg, Lena E, Nielsen, Elisabet I, Wang, Mikala, and Schrøder, Henrik
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- 2018
14. Advanced methods for dose and regimen finding during drug development:Summary of the EMA /EFPIA workshop on dose finding (London 4-5 December 2014)
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Musuamba, F. T., Manolis, E., Holford, N., Cheung, S. Y. A., Friberg, Lena E, Ogungbenro, K., Posch, M., Yates, J. W. T., Berry, S., Thomas, N., Corriol-Rohou, S., Bornkamp, B., Bretz, F., Hooker, Andrew, Van der Graaf, P. H., Standing, J. F., Hay, J., Cole, S., Gigante, V., Karlsson, K., Dumortier, T., Benda, N., Serone, F., Das, S., Brochot, A., Ehmann, F., Hemmings, R., and Rusten, I. Skottheim
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Clinical Trials as Topic ,Dose-Response Relationship, Drug ,Pharmaceutical Preparations ,Research Design ,Drug Discovery ,White Paper ,Animals ,Humans ,Pharmacology and Toxicology ,Models, Theoretical ,Farmakologi och toxikologi - Abstract
Inadequate dose selection for confirmatory trials is currently still one of the most challenging issues in drug development, as illustrated by high rates of late-stage attritions in clinical development and postmarketing commitments required by regulatory institutions. In an effort to shift the current paradigm in dose and regimen selection and highlight the availability and usefulness of well-established and regulatory-acceptable methods, the European Medicines Agency (EMA) in collaboration with the European Federation of Pharmaceutical Industries Association (EFPIA) hosted a multistakeholder workshop on dose finding (London 4-5 December 2014). Some methodologies that could constitute a toolkit for drug developers and regulators were presented. These methods are described in the present report: they include five advanced methods for data analysis (empirical regression models, pharmacometrics models, quantitative systems pharmacology models, MCP-Mod, and model averaging) and three methods for study design optimization (Fisher information matrix (FIM)-based methods, clinical trial simulations, and adaptive studies). Pairwise comparisons were also discussed during the workshop; however, mostly for historical reasons. This paper discusses the added value and limitations of these methods as well as challenges for their implementation. Some applications in different therapeutic areas are also summarized, in line with the discussions at the workshop. There was agreement at the workshop on the fact that selection of dose for phase III is an estimation problem and should not be addressed via hypothesis testing. Dose selection for phase III trials should be informed by well-designed dose-finding studies; however, the specific choice of method(s) will depend on several aspects and it is not possible to recommend a generalized decision tree. There are many valuable methods available, the methods are not mutually exclusive, and they should be used in conjunction to ensure a scientifically rigorous understanding of the dosing rationale.
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- 2017
15. Item Response Theory to Quantify Longitudinal Placebo and Paliperidone Effects on PANSS Scores in Schizophrenia
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Krekels, E. H. J., Novakovic, Ana M., Vermeulen, A. M., Friberg, Lena E, and Karlsson, Mats O.
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Psychiatry ,Pharmacology and Toxicology ,Farmakologi och toxikologi ,Psykiatri - Abstract
As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data discards information and violates the numerical nature of the scale. Here a longitudinal analysis based on Item Response Theory is presented using PANSS data from phase III clinical trials. Latent disease severity variables were derived from item-level data on the positive, negative, and general PANSS subscales each. On all subscales, the time course of placebo responses were best described with Weibull models, and dose-independent functions with exponential models to describe the onset of the full effect were used to describe paliperidone's effect. Placebo and drug effect were most pronounced on the positive subscale. The final model successfully describes the time course of treatment effects on the individual PANSS item-levels, on all PANSS subscale levels, and on the total score level.
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- 2017
16. Colistin Pharmacokinetics after Application of a Loading Dose of 9 MU Colistin Methanesulfonate (CMS) in Critically Ill Patients Receiving Continuous Venovenous Hemodiafiltration (CVVHDF)
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Karaiskos, Ilias, Friberg, Lena E, Ioannidis, Konstantinos, Galani, Lamprini, Baziaka, Fotini, Barmpouti, Eleftheria, Paskalis Harris, and Giamarellou, Helen
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- 2014
- Full Text
- View/download PDF
17. Pharmacokinetic-Pharmacodynamic Modelling of Anticancer Drugs : Haematological Toxicity and Tumour Response in Hollow Fibres
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Friberg, Lena E
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Pharmaceutical Sciences ,Pharmacokinetics/Pharmacotherapy ,Farmakokinetik/Farmakoterapi ,Farmaceutiska vetenskaper - Abstract
Established quantitative relationships between dose, plasma concentrations and response [pharmacokinetic-pharmacodynamic (PKPD) models] have a high potential in improving therapeutic indices of anticancer drug therapy and in increasing drug development efficiency. PKPD modelling is a helpful tool for characterising and understanding schedule dependence. The aim of this thesis was to develop PKPD models of anticancer drugs for tumour effects and haematological toxicity, which is the most frequent dose-limiting toxicity. PK and haematological toxicity after several schedules were studied in rats and semi-physiological PKPD models for the whole time course of myelosuppression were developed from animal and patient data. The possibility to implant hollow fibres filled with tumour cells in immunocompetent rats was investigated for simultaneous assessment of PK, tumour response and haematological toxicity. Population data analyses were performed using the software NONMEM. When all injections were administered within eight hours, fractionated schedules of 5-fluorouracil and epirubicin produced similar haematological toxicity in rats as a single dose, when the non-linear PK of 5-fluorouracil was accounted for. When the time interval was extended to two days for 5-fluorouracil, the fractionated regimens were more toxic. The developed semi-physiological PKPD models included transit compartments that mimic maturation stages in bone marrow and explain the time lag. Feedback mechanisms characterised the rebound. The models successfully described myelosuppression in patients (DMDC) and rats (5-fluorouracil), after different administration schedules. Further developments made it possible to characterise the time course of myelosuppression after administration of each one of six different drugs, with parameters related to the haematopoietic system consistent across drugs. The developed hollow fibre model in immunocompetent rats was successfully applied to monitor PK, toxicity and the time course of antitumour effects. PKPD modelling illustrated that the schedule dependence of the anticancer agent CHS 828 is partly due to dose-dependent bioavailability and partly due to a schedule-dependent PD effect.
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- 2003
18. In vivo fitness of carbapenem-resistant Acinetobacter baumannii strains in murine infection is associated with treatment failure in human infections
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Nizar Andria, Anat Stern, Nadya Rakovitsky, Lena E. Friberg, Rosa Zampino, Amos Adler, Yael Zak-Doron, Yehuda Carmeli, Patrizia Murino, Noa Eliakim, Roni Bitterman, Lorenzo Bertolino, Giuseppe Giuffre, Jonathan Lellouche, Mariano Bernardo, Antonio Corcione, Antigoni Kotsaki, Hiba Zayyad, Anastasia Antoniadou, Johan W. Mouton, Tanya Babich, Neta Petersiel, Amir Karban, Domenico Iossa, Giuseppe Ruocco, Vered Daitch, Ami Neuberger, Oren Zusman, George L. Daikos, Sergey Altunin, Roberto Giurazza, Noa Eliakim-Raz, Ursula Theuretzbacher, Yael Dishon, Mical Paul, Emanuele Durante-Mangoni, Yael Dishon Benattar, Dafna Yahav, Leonard Leibovici, Anna Skiada, Inbar Levi, Michal Elbaz, Giusi Cavezza, Heyam Atamna, Elizabeth Temkin, Amichay Hameir, Amir Nutman, Yaakov Dickstein, Marina Raines, Roberto Andini, Fidi Koppel, Maria Galdo, Ioannis Pavleas, Adriano Cristinziano, Nutman, Amir, Temkin, Elizabeth, Lellouche, Jonathan, Rakovitsky, Nadya, Hameir, Amichay, Daikos, George, Durante-Mangoni, Emanuele, Pavleas, Ioanni, Dishon, Yael, Petersiel, Neta, Yahav, Dafna, Eliakim, Noa, Bernardo, Mariano, Iossa, Domenico, Friberg, Lena E, Theuretzbacher, Ursula, Leibovici, Leonard, Paul, Mical, and Carmeli, Yehuda
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Acinetobacter baumannii ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,animal structures ,Urinary system ,030106 microbiology ,Microbial Sensitivity Tests ,Logistic regression ,law.invention ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,law ,Internal medicine ,Drug Resistance, Bacterial ,medicine ,Animals ,Humans ,Treatment Failure ,030212 general & internal medicine ,biology ,Bacterial fitne ,Clinical outcome ,business.industry ,food and beverages ,General Medicine ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,Intensive care unit ,Anti-Bacterial Agents ,body regions ,Pneumonia ,Infectious Diseases ,Carbapenems ,Murine thigh infection model ,Carbapenem-resistant Acinetobacter baumannii ,SOFA score ,business ,Carbapenem resistant Acinetobacter baumannii ,Acinetobacter Infections - Abstract
Objectives Mortality among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections varies between studies. We examined whether in vivo fitness of CRAB strains is associated with clinical outcomes in patients with CRAB infections. Methods Isolates were collected from patients enrolled in the AIDA trial with hospital-acquired pneumonia, bloodstream infections and/or urinary tract infections caused by CRAB. The primary outcome was 14-day clinical failure, defined as failure to meet all criteria: alive; haemodynamically stable; improved or stable Sequential Organ Failure Assessment (SOFA) score; improved or stable oxygenation; and microbiological cure of bacteraemia. The secondary outcome was 14-day mortality. We tested in vivo growth using a neutropenic murine thigh infection model. Fitness was defined based on the CFU count 24 hours after injection of an inoculum of 105 CFU. We used mixed-effects logistic regression to test the association between fitness and the two outcomes. Results The sample included 266 patients; 215 (80.8%) experienced clinical failure. CRAB fitness ranged from 5.23 to 10.08 log CFU/g. The odds of clinical failure increased by 62% for every 1-log CFU/g increase in fitness (OR 1.62, 95% CI 1.04–2.52). After adjusting for age, Charlson score, SOFA score and acquisition in the intensive care unit, fitness remained significant (adjusted OR 1.63, 95% CI 1.03–2.59). CRAB fitness had a similar effect on 14-day mortailty, although the association was not statistically significant (OR 1.56, 95% CI 0.95–2.57). It became significant after adjusting for age, Charlson score, SOFA score and recent surgery (adjusted OR 1.88, 95% CI 1.09–3.25). Conclusions In vivo CRAB fitness was associated with clinical failure in patients with CRAB infection.
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- 2022
19. Model‐Informed Drug Development for Antimicrobials: Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin
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Sha Cao, Diarmaid Hughes, Carina Vingsbo Lundberg, Sven N. Hobbie, Solveiga Grinberga, Edgars Liepinsh, Anna Petersson, Malgorzata Urbas, Paraskevi Giachou, Tomás Sou, Dorota Zabicka, Maria Backlund, Jon Hansen, Lena E. Friberg, Magdalena Tomczak, Onur Ercan, University of Zurich, and Friberg, Lena E
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Guinea Pigs ,610 Medicine & health ,Pharmacology ,Apramycin ,030226 pharmacology & pharmacy ,Models, Biological ,Article ,03 medical and health sciences ,Pharmaceutical Sciences ,Mice ,0302 clinical medicine ,Dogs ,Pharmacokinetics ,In vivo ,medicine ,Escherichia coli ,2736 Pharmacology (medical) ,Animals ,Nebramycin ,Pharmacology (medical) ,PK/PD models ,Volume of distribution ,Bacteriological Techniques ,Dose-Response Relationship, Drug ,Chemistry ,10179 Institute of Medical Microbiology ,Research ,Aminoglycoside ,Articles ,Farmaceutiska vetenskaper ,Anti-Bacterial Agents ,Rats ,3004 Pharmacology ,Drug development ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Area Under Curve ,570 Life sciences ,biology ,medicine.drug - Abstract
Apramycin represents a subclass of aminoglycoside antibiotics that has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. Model-informed drug development may facilitate its transition from preclinical to clinical phase. This study explored the potential of pharmacokinetic/pharmacodynamic (PK/PD) modeling to maximize the use of in vitro time-kill and in vivo preclinical data for prediction of a human efficacious dose (HED) for apramycin. PK model parameters of apramycin from four different species (mouse, rat, guinea pig, and dog) were allometrically scaled to humans. A semimechanistic PK/PD model was developed from the rich in vitro data on four Escherichia coli strains and subsequently the sparse in vivo efficacy data on the same strains were integrated. An efficacious human dose was predicted from the PK/PD model and compared with the classical PK/PD index methodology and the aminoglycoside dose similarity. One-compartment models described the PK data and human values for clearance and volume of distribution were predicted to 7.07 L/hour and 26.8 L, respectively. The required fAUC/MIC (area under the unbound drug concentration-time curve over MIC ratio) targets for stasis and 1-log kill in the thigh model were 34.5 and 76.2, respectively. The developed PK/PD model predicted the efficacy data well with strain-specific differences in susceptibility, maximum bacterial load, and resistance development. All three dose prediction approaches supported an apramycin daily dose of 30 mg/kg for a typical adult patient. The results indicate that the mechanistic PK/PD modeling approach can be suitable for HED prediction and serves to efficiently integrate all available efficacy data with potential to improve predictive capacity.
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- 2020
20. Large-scale WGS of carbapenem-resistant Acinetobacter baumannii isolates reveals patterns of dissemination of ST clades associated with antibiotic resistance
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Sammy Frenk, Elizabeth Temkin, Mor N. Lurie-Weinberger, Alona Keren-Paz, Reut Rov, Nadya Rakovitsky, Liat Wullfhart, Amir Nutman, George L. Daikos, Anna Skiada, Emanuele Durante-Mangoni, Yael Dishon Benattar, Roni Bitterman, Dafna Yahav, Vered Daitch, Mariano Bernardo, Domenico Iossa, Oren Zusman, Lena E. Friberg, Johan W. Mouton, Ursula Theuretzbacher, Leonard Leibovici, Yuval Geffen, Rina Gershon, Mical Paul, Yehuda Carmeli, Frenk, Sammy, Temkin, Elizabeth, Lurie-Weinberger, Mor N, Keren-Paz, Alona, Rov, Reut, Rakovitsky, Nadya, Wullfhart, Liat, Nutman, Amir, Daikos, George L, Skiada, Anna, Durante-Mangoni, Emanuele, Dishon Benattar, Yael, Bitterman, Roni, Yahav, Dafna, Daitch, Vered, Bernardo, Mariano, Iossa, Domenico, Zusman, Oren, Friberg, Lena E, Mouton, Johan W, Theuretzbacher, Ursula, Leibovici, Leonard, Geffen, Yuval, Gershon, Rina, Paul, Mical, and Carmeli, Yehuda
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Pharmacology ,Microbiology (medical) ,Acinetobacter baumannii ,Microbial Sensitivity Tests ,beta-Lactamases ,Anti-Bacterial Agents ,Infectious Diseases ,Bacterial Proteins ,Carbapenems ,Drug Resistance, Multiple, Bacterial ,Humans ,Pharmacology (medical) ,Acinetobacter Infections ,Multilocus Sequence Typing - Abstract
Objectives To describe the population genetics and antibiotic resistance gene distribution of carbapenem-resistant Acinetobacter baumannii (CRAB) isolates causing infections in three Mediterranean countries. Methods Isolates were collected during the 2013–17 AIDA clinical trial in six hospitals in Israel, Greece and Italy. WGS, bioinformatic characterization and antibiotic resistance profiling were performed. Results In the 247 CRAB isolates characterized in this study, ST distribution varied by country: 29/31 (93.5%) Greek isolates, 34/41 (82.9%) Italian isolates and 70/175 (40.0%) Israeli isolates belonged to ST2. The identified ST2 isolates included eight distinct clades: 2C, 2D and 2H were significantly more common in Italy, while 2F was unique to Greece. The uncommon ST3 was not present among Greek isolates and constituted only 5/41 (12%) Italian isolates. On the other hand, it was much more common among Israeli isolates: 78/175 (44.6%) belonged to ST3. The vast majority of isolates, 240/247 (97.2%), were found to harbour acquired carbapenemases, primarily blaOXA-23. The chromosomal oxaAb (blaOXA-51-like) and ampC genes characteristic of this organism were also ubiquitous. Most (96.4%) ST3 isolates carried a broad-host-range plasmid IncP1α. Conclusions The geographical differences in CRAB populations support the theory that clonal spread of CRAB leads to endemicity in hospitals and regions. The close association between antibiotic resistance genes and clades, and between plasmids and STs, suggest that de novo creation of MDR A. baumannii is rare. The clustering of antibiotic resistance genes and plasmids that is unique to each clade/ST, and nearly uniform within clades/STs, suggests that horizontal transmission is rare but crucial to the clade’s/ST’s success.
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- 2021
21. Reply to Wilson et al
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Mical Paul, Yehuda Carmeli, George L. Daikos, Leonard Leibovici, Emanuele Durante-Mangoni, Lena E. Friberg, Yaakov Dickstein, Dickstein, Yaakov, Leibovici, Leonard, Carmeli, Yehuda, Daikos, George, Durante-Mangoni, Emanuele, Friberg, Lena E, and Paul, Mical
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Microbiology (medical) ,Infectious Diseases ,Psychoanalysis ,business.industry ,MEDLINE ,Medicine ,business - Published
- 2020
22. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial
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Johan W. Mouton, Tanya Babich, George L. Daikos, Roni Bitterman, Emanuele Durante-Mangoni, Yael Dishon Benattar, Mical Paul, Vered Daitch, Hiba Zayyad, Rosa Zampino, Amos Adler, Oren Zusman, Roberto Andini, Lena E. Friberg, Fidi Koppel, Pia Clara Pafundi, Yaakov Dickstein, Yehuda Carmeli, Noa Eliakim-Raz, Amir Nutman, Dafna Yahav, Ursula Theuretzbacher, Anastasia Antoniadou, Leonard Leibovici, Anna Skiada, Ioannis Pavleas, Inbar Levi, Medical Microbiology & Infectious Diseases, Paul, Mical, Daikos, George L., Durante-Mangoni, Emanuele, Yahav, Dafna, Carmeli, Yehuda, Benattar, Yael Dishon, Skiada, Anna, Andini, Roberto, Eliakim-Raz, Noa, Nutman, Amir, Zusman, Oren, Antoniadou, Anastasia, Pafundi, Pia Clara, Adler, Amo, Dickstein, Yaakov, Pavleas, Ioanni, Zampino, Rosa, Daitch, Vered, Bitterman, Roni, Zayyad, Hiba, Koppel, Fidi, Levi, Inbar, Babich, Tanya, Friberg, Lena E., Mouton, Johan W., Theuretzbacher, Ursula, and Leibovici, Leonard
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0301 basic medicine ,medicine.medical_specialty ,Combination therapy ,biology ,business.industry ,030106 microbiology ,bacterial infections and mycoses ,medicine.disease ,biology.organism_classification ,Loading dose ,Meropenem ,law.invention ,Acinetobacter baumannii ,03 medical and health sciences ,Pneumonia ,Infectious Diseases ,Pharmacotherapy ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Colistin ,business ,medicine.drug - Abstract
Summary Background Colistin–carbapenem combinations are synergistic in vitro against carbapenem-resistant Gram-negative bacteria. We aimed to test whether combination therapy improves clinical outcomes for adults with infections caused by carbapenem-resistant or carbapenemase-producing Gram-negative bacteria. Methods A randomised controlled superiority trial was done in six hospitals in Israel, Greece, and Italy. We included adults with bacteraemia, ventilator-associated pneumonia, hospital-acquired pneumonia, or urosepsis caused by carbapenem-non-susceptible Gram-negative bacteria. Patients were randomly assigned (1:1) centrally, by computer-generated permuted blocks stratified by centre, to intravenous colistin (9-million unit loading dose, followed by 4·5 million units twice per day) or colistin with meropenem (2-g prolonged infusion three times per day). The trial was open-label, with blinded outcome assessment. Treatment success was defined as survival, haemodynamic stability, improved or stable Sequential Organ Failure Assessment score, stable or improved ratio of partial pressure of arterial oxygen to fraction of expired oxygen for patients with pneumonia, and microbiological cure for patients with bacteraemia. The primary outcome was clinical failure, defined as not meeting all success criteria by intention-to-treat analysis, at 14 days after randomisation. This trial is registered at ClinicalTrials.gov, number NCT01732250, and is closed to accrual. Findings Between Oct 1, 2013, and Dec 31, 2016, we randomly assigned 406 patients to the two treatment groups. Most patients had pneumonia or bacteraemia (355/406, 87%), and most infections were caused by Acinetobacter baumannii (312/406, 77%). No significant difference between colistin monotherapy (156/198, 79%) and combination therapy (152/208, 73%) was observed for clinical failure at 14 days after randomisation (risk difference −5·7%, 95% CI −13·9 to 2·4; risk ratio [RR] 0·93, 95% CI 0·83–1·03). Results were similar among patients with A baumannii infections (RR 0·97, 95% CI 0·87–1·09). Combination therapy increased the incidence of diarrhoea (56 [27%] vs 32 [16%] patients) and decreased the incidence of mild renal failure (37 [30%] of 124 vs 25 [20%] of 125 patients at risk of or with kidney injury). Interpretation Combination therapy was not superior to monotherapy. The addition of meropenem to colistin did not improve clinical failure in severe A baumannii infections. The trial was unpowered to specifically address other bacteria. Funding EU AIDA grant Health-F3-2011-278348.
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- 2018
23. Colistin Resistance Development Following Colistin-Meropenem Combination Therapy Versus Colistin Monotherapy in Patients With Infections Caused by Carbapenem-Resistant Organisms
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Yehuda Carmeli, Emanuele Durante-Mangoni, Leonard Leibovici, Anna Skiada, Jonathan Lellouche, Nadya Rakovitsky, Lena E. Friberg, Mical Paul, Dafna Yahav, Sergey Altunin, Anastasia Antoniadou, Amir Nutman, Mariano Bernardo, Yaakov Dickstein, Johan W. Mouton, Vered Daitch, Ioannis Deliolanis, Domenico Iossa, Yael Dishon Benattar, David Schwartz, George L. Daikos, Viktor Rognås, Medical Microbiology & Infectious Diseases, Dickstein, Yaakov, Lellouche, Jonathan, Schwartz, David, Nutman, Amir, Rakovitsky, Nadya, Dishon Benattar, Yael, Altunin, Sergey, Bernardo, Mariano, Iossa, Domenico, Durante-Mangoni, Emanuele, Antoniadou, Anastasia, Skiada, Anna, Deliolanis, Ioanni, Daikos, George L, Daitch, Vered, Yahav, Dafna, Leibovici, Leonard, Rognås, Viktor, Friberg, Lena E, Mouton, Johan W, Paul, Mical, and Carmeli, Yehuda
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0301 basic medicine ,Microbiology (medical) ,Carbapenem ,medicine.medical_specialty ,Infectious Medicine ,Combination therapy ,030106 microbiology ,Resistance ,Infektionsmedicin ,Microbial Sensitivity Tests ,Meropenem ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Enterobacteriaceae ,law ,Internal medicine ,Gram-Negative Bacteria ,medicine ,polycyclic compounds ,Humans ,030212 general & internal medicine ,biology ,business.industry ,Colistin ,Incidence (epidemiology) ,Hazard ratio ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,bacterial infections and mycoses ,Gram-negative ,Anti-Bacterial Agents ,Infectious Diseases ,Carbapenems ,bacteria ,lipids (amino acids, peptides, and proteins) ,business ,medicine.drug - Abstract
Background We evaluated whether carbapenem-colistin combination therapy reduces the emergence of colistin resistance, compared to colistin monotherapy, when given to patients with infections due to carbapenem-resistant Gram-negative organisms. Methods This is a pre-planned analysis of a secondary outcome from a randomized, controlled trial comparing colistin monotherapy with colistin-meropenem combination for the treatment of severe infections caused by carbapenem-resistant, colistin-susceptible Gram-negative bacteria. We evaluated rectal swabs taken on Day 7 or later for the presence of new colistin-resistant (ColR) isolates. We evaluated the emergence of any ColR isolate and the emergence of ColR Enterobacteriaceae (ColR-E). Results Data were available for 214 patients for the primary analysis; emergent ColR organisms were detected in 22 (10.3%). No difference was observed between patients randomized to treatment with colistin monotherapy (10/106, 9.4%) versus patients randomized to colistin-meropenem combination therapy (12/108, 11.1%; P = .669). ColR-E organisms were detected in 18/249 (7.2%) patients available for analysis. No difference was observed between the 2 treatment arms (colistin monotherapy 6/128 [4.7%] vs combination therapy 12/121 [9.9%]; P = .111). Enterobacteriaceae, as the index isolate, was found to be associated with development of ColR-E (hazard ratio, 3.875; 95% confidence interval, 1.475–10.184; P = .006). Conclusions Carbapenem-colistin combination therapy did not reduce the incidence of colistin resistance emergence in patients with infections due to carbapenem-resistant organisms. Further studies are necessary to elucidate the development of colistin resistance and methods for its prevention.
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- 2019
24. A whole-body physiologically based pharmacokinetic (WB-PBPK) model of ciprofloxacin: a step towards predicting bacterial killing at sites of infection
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Mats O. Karlsson, Dalia Khachman, Jean-Marie Conil, Lena E. Friberg, Georges Houin, Elisabet I. Nielsen, Céline M. Laffont, Muhammad Waqas Sadiq, Bernard Georges, Department of Pharmaceutical Biosciences, Uppsala University, AstraZeneca, ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Universitaire de Purpan (CHU Purpan), Hôpital de Rangueil, CHU Toulouse [Toulouse], This work was supported by the Swedish Foundation for Strategic Research and DDMoRe which is an Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. The DDMoRe project is also supported by financial contribution from Academic and SME partners., and Friberg, Lena E.
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0301 basic medicine ,Male ,Physiologically based pharmacokinetic modelling ,medicine.drug_class ,[SDV]Life Sciences [q-bio] ,030106 microbiology ,Antibiotics ,Informative priors ,Pharmacokinetic-pharmacodynamic ,Pharmacology ,Biology ,Models, Biological ,Microbiology ,Pharmaceutical Sciences ,03 medical and health sciences ,Pharmacokinetics ,Fluoroquinolone ,In vivo ,Ciprofloxacin ,medicine ,Escherichia coli ,Distribution (pharmacology) ,Humans ,Computer Simulation ,Tissue Distribution ,Pharmaceutical sciences ,Physiologically-based pharmacokinetic ,Escherichia coli Infections ,NONMEM ,Original Paper ,Antibiotic ,Modeling ,Middle Aged ,Farmaceutiska vetenskaper ,3. Good health ,Anti-Bacterial Agents ,Area Under Curve ,modeling ,informative priors ,fluoroquinolone ,bacterial infection ,antibiotic ,Female ,Bacterial infection ,medicine.drug - Abstract
The purpose of this study was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model for ciprofloxacin for ICU patients, based on only plasma concentration data. In a next step, tissue and organ concentration time profiles in patients were predicted using the developed model. The WB-PBPK model was built using a non-linear mixed effects approach based on data from 102 adult intensive care unit patients. Tissue to plasma distribution coefficients (Kp) were available from the literature and used as informative priors. The developed WB-PBPK model successfully characterized both the typical trends and variability of the available ciprofloxacin plasma concentration data. The WB-PBPK model was thereafter combined with a pharmacokinetic–pharmacodynamic (PKPD) model, developed based on in vitro time-kill data of ciprofloxacin and Escherichia coli to illustrate the potential of this type of approach to predict the time-course of bacterial killing at different sites of infection. The predicted unbound concentration–time profile in extracellular tissue was driving the bacterial killing in the PKPD model and the rate and extent of take-over of mutant bacteria in different tissues were explored. The bacterial killing was predicted to be most efficient in lung and kidney, which correspond well to ciprofloxacin’s indications pneumonia and urinary tract infections. Furthermore, a function based on available information on bacterial killing by the immune system in vivo was incorporated. This work demonstrates the development and application of a WB-PBPK–PD model to compare killing of bacteria with different antibiotic susceptibility, of value for drug development and the optimal use of antibiotics . Electronic supplementary material The online version of this article (doi:10.1007/s10928-016-9486-9) contains supplementary material, which is available to authorized users.
- Published
- 2016
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