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Kristoffersson, AndersORCID iD iconorcid.org/0000-0003-3166-9981
Alternative names
Publications (10 of 16) Show all publications
Maarbjerg, S. F., Thorsted, A., Kristoffersson, A., Friberg, L. E., Nielsen, E. I., Wang, M., . . . Schroder, H. (2019). Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?. Pediatric Blood & Cancer, 66(6), Article ID e27654.
Open this publication in new window or tab >>Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?
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2019 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 66, no 6, article id e27654Article in journal (Refereed) Published
Abstract [en]

Background

Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens.

Procedure

This prospective pharmacokinetic study was conducted from April 2016 to January 2018. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4x MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range.

Results

A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4x MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC <= 8 mg/L.

Conclusions

Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.

Keywords
cancer, febrile neutropenia, pediatric, pharmacokinetics, piperacillin, target attainment
National Category
Pediatrics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-383501 (URN)10.1002/pbc.27654 (DOI)000465150800066 ()30740885 (PubMedID)
Available from: 2019-05-17 Created: 2019-05-17 Last updated: 2019-05-17Bibliographically approved
Thorsted, A., Kristoffersson, A. N., Maarbjerg, S. F., Schrøder, H., Wang, M., Brock, B., . . . Friberg, L. E. (2019). Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen. Journal of Antimicrobial Chemotherapy, 74(10), 2984-2993
Open this publication in new window or tab >>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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2019 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 74, no 10, p. 2984-2993Article in journal (Refereed) Published
Abstract [en]

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>1xMIC and 50% fT>4xMIC) 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 15.4L/h (70kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT>4xMIC was achieved for an MIC of 4.0mg/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 100mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT>1xMIC due to the rapid piperacillin elimination.

Conclusions The licensed dose for children with febrile neutropenia (80mg/kg q6h as a 30min 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>1xMIC) or prolonged infusions (50% fT>4xMIC).

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396736 (URN)10.1093/jac/dkz270 (DOI)000491253800023 ()31273375 (PubMedID)
Funder
Swedish Research Council, 2015-06826
Available from: 2019-11-26 Created: 2019-11-26 Last updated: 2019-11-26Bibliographically approved
Andersen, M. G., Thorsted, A., Storgaard, M., Kristoffersson, A. N., Friberg, L. E. & Öbrink-Hansen, K. (2018). Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?. Antimicrobial Agents and Chemotherapy, 62(5), Article ID e02306.
Open this publication in new window or tab >>Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?
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2018 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 5, article id e02306Article in journal (Refereed) Published
Abstract [en]

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC (fTMIC) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCLCR) and constituted 74% of the total clearance in a typical individual (eCLCR, 83.9 ml/min). Patients with a high eCLCR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fTMIC) and 0.125 mg/liter (100% fTMIC). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2018
Keywords
augmented renal clearance, dosage optimization, piperacillin, population pharmacokinetics, sepsis
National Category
Infectious Medicine Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-356077 (URN)10.1128/AAC.02306-17 (DOI)000431341200054 ()29507062 (PubMedID)
Available from: 2018-07-13 Created: 2018-07-13 Last updated: 2018-07-13Bibliographically approved
Khan, D., Lagerbäck, P., Malmberg, C., Kristoffersson, A., Gullberg, E., Cao, S., . . . Friberg, L. E. (2018). Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli. International Journal of Antimicrobial Agents, 51(3), 399-406, Article ID S0924-8579(17)30392-8.
Open this publication in new window or tab >>Predicting mutant selection in competition experiments with ciprofloxacin-exposed Escherichia coli
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2018 (English)In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 51, no 3, p. 399-406, article id S0924-8579(17)30392-8Article in journal (Refereed) Published
Abstract [en]

Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.

Keywords
Ciprofloxacin, Escherichia coli, PK/PD modelling, PK/PD predictions, Pharmacokinetics/Pharmacodynamics, Time–kill experiments
National Category
Pharmaceutical Sciences Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-343607 (URN)10.1016/j.ijantimicag.2017.10.019 (DOI)000427582000016 ()29127049 (PubMedID)
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme, FP7/2007-2013
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2018-05-18Bibliographically approved
Brill, M. J. E., Kristoffersson, A., Zhao, C., Nielsen, E. I. & Friberg, L. E. (2018). Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations. Clinical Microbiology and Infection, 24(7), 697-706
Open this publication in new window or tab >>Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations
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2018 (English)In: Clinical Microbiology and Infection, ISSN 1198-743X, E-ISSN 1469-0691, Vol. 24, no 7, p. 697-706Article, review/survey (Refereed) Published
Abstract [en]

Background: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. Aims: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. Sources: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. Content: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens.

Keywords
Antibiotics, Drug combinations, Interaction, Semi-mechanistic pharmacokinetic-pharmacodynamic modelling, Simulations
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-366616 (URN)10.1016/j.cmi.2017.11.023 (DOI)000436640800008 ()29229429 (PubMedID)
Funder
Swedish Research Council, 2015-06826EU, FP7, Seventh Framework Programme, Health-F3-2011-278348
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved
Mohamed, A. F., Kristoffersson, A., Karvanen, M., Nielsen, E., Cars, O. & Friberg, L. (2016). Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model. Journal of Antimicrobial Chemotherapy, 71(5), 1279-1290
Open this publication in new window or tab >>Dynamic interaction of colistin and meropenem on a WT and a resistant strain of Pseudomonas aeruginosa as quantified in a PK/PD model
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2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 5, p. 1279-1290Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.

METHODS: In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem.

RESULTS: A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h.

CONCLUSIONS: The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance.

National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-278022 (URN)10.1093/jac/dkv488 (DOI)000376291300021 ()26850719 (PubMedID)
Funder
Swedish Foundation for Strategic Research EU, FP7, Seventh Framework Programme
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved
Dickstein, Y., Leibovici, L., Yahav, D., Eliakim-Raz, N., Daikos, G. L., Skiada, A., . . . Paul, M. (2016). Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open, 6(4), Article ID e009956.
Open this publication in new window or tab >>Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol
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2016 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 6, no 4, article id e009956Article in journal (Refereed) Published
Abstract [en]

Introduction: The emergence of antibiotic-resistant bacteria has driven renewed interest in older antibacterials, including colistin. Previous studies have shown that colistin is less effective and more toxic than modern antibiotics. In vitro synergy studies and clinical observational studies suggest a benefit of combining colistin with a carbapenem. A randomised controlled study is necessary for clarification. Methods and analysis: This is a multicentre, investigator-initiated, open-label, randomised controlled superiority 1:1 study comparing colistin monotherapy with colistin-meropenem combination therapy for infections caused by carbapenem-resistant Gram-negative bacteria. The study is being conducted in 6 centres in 3 countries (Italy, Greece and Israel). We include patients with hospital-associated and ventilator-associated pneumonia, bloodstream infections and urosepsis. The primary outcome is treatment success at day 14, defined as survival, haemodynamic stability, stable or improved respiratory status for patients with pneumonia, microbiological cure for patients with bacteraemia and stability or improvement of the Sequential Organ Failure Assessment (SOFA) score. Secondary outcomes include 14-day and 28-day mortality as well as other clinical end points and safety outcomes. A sample size of 360 patients was calculated on the basis of an absolute improvement in clinical success of 15% with combination therapy. Outcomes will be assessed by intention to treat. Serum colistin samples are obtained from all patients to obtain population pharmacokinetic models. Microbiological sampling includes weekly surveillance samples with analysis of resistance mechanisms and synergy. An observational trial is evaluating patients who met eligibility requirements but were not randomised in order to assess generalisability of findings. Ethics and dissemination: The study was approved by ethics committees at each centre and informed consent will be obtained for all patients. The trial is being performed under the auspices of an independent data and safety monitoring committee and is included in a broad dissemination strategy regarding revival of old antibiotics.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-298702 (URN)10.1136/bmjopen-2015-009956 (DOI)000376391400033 ()27098822 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, Health-F3-2011-278348
Available from: 2016-07-07 Created: 2016-07-06 Last updated: 2017-11-28Bibliographically approved
Kristoffersson, A., David-Pierson, P., Parrott, N. J., Kuhlmann, O., Lave, T., Friberg, L. & Nielsen, E. (2016). Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs. Pharmaceutical research, 33(5), 1115-1125
Open this publication in new window or tab >>Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs
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2016 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 33, no 5, p. 1115-1125Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.

METHODS: A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.

RESULTS: The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2.

CONCLUSIONS: A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.

National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-278027 (URN)10.1007/s11095-016-1856-x (DOI)000373629000006 ()26786016 (PubMedID)
External cooperation:
Funder
Swedish Foundation for Strategic Research
Available from: 2016-02-23 Created: 2016-02-23 Last updated: 2018-01-10Bibliographically approved
Kristoffersson, A. N., Friberg, L. E. & Nyberg, J. (2015). Inter occasion variability in individual optimal design. Journal of Pharmacokinetics and Pharmacodynamics, 42(6), 735-750
Open this publication in new window or tab >>Inter occasion variability in individual optimal design
2015 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 42, no 6, p. 735-750Article in journal (Refereed) Published
Abstract [en]

Inter occasion variability (IOV) is of importance to consider in the development of a design where individual pharmacokinetic or pharmacodynamic parameters are of interest. IOV may adversely affect the precision of maximum a posteriori (MAP) estimated individual parameters, yet the influence of inclusion of IOV in optimal design for estimation of individual parameters has not been investigated. In this work two methods of including IOV in the maximum a posteriori Fisher information matrix (FIMMAP) are evaluated: (i) MAP(occ)-the IOV is included as a fixed effect deviation per occasion and individual, and (ii) POPocc-the IOV is included as an occasion random effect. Sparse sampling schedules were designed for two test models and compared to a scenario where IOV is ignored, either by omitting known IOV (Omit) or by mimicking a situation where unknown IOV has inflated the IIV (Inflate). Accounting for IOV in the FIMMAP markedly affected the designs compared to ignoring IOV and, as evaluated by stochastic simulation and estimation, resulted in superior precision in the individual parameters. In addition MAP(occ) and POPocc accurately predicted precision and shrinkage. For the investigated designs, the MAP(occ) method was on average slightly superior to POPocc and was less computationally intensive.

Keywords
Inter occasion variability (IOV), Optimal design (OD), Maximum a posteriori (MAP), Fisher information, Bayesian, Pharmacometrics, Shrinkage
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-268393 (URN)10.1007/s10928-015-9449-6 (DOI)000363982800010 ()26452548 (PubMedID)
Funder
Swedish Research CouncilEU, European Research Council, Health-F3-2011-278348
Available from: 2015-12-09 Created: 2015-12-04 Last updated: 2018-01-10Bibliographically approved
Kristoffersson, A. (2015). Study Design and Dose Regimen Evaluation of Antibiotics based on Pharmacokinetic and Pharmacodynamic Modelling. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Study Design and Dose Regimen Evaluation of Antibiotics based on Pharmacokinetic and Pharmacodynamic Modelling
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Current excessive use and abuse of antibiotics has resulted in increasing bacterial resistance to common treatment options which is threatening to deprive us of a pillar of modern medicine. In this work methods to optimize the use of existing antibiotics and to help development of new antibiotics were developed and applied.

Semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) models were developed to describe the time course of the dynamic effect and interaction of combinations of antibiotics. The models were applied to illustrate that colistin combined with a high dose of meropenem may overcome meropenem-resistant P. aeruginosa infections.

The results from an in vivo dose finding study of meropenem was successfully predicted by the meropenem PKPD model in combination with a murine PK model, which supports model based dosage selection. However, the traditional PK/PD index based dose selection was predicted to have poor extrapolation properties from pre-clinical to clinical settings, and across patient populations.

The precision of the model parameters, and hence the model predictions, is dependent on the experimental design. A limited study design is dictated by cost and, for in vivo studies, ethical reasons. In this work optimal design (OD) was demonstrated to be able to reduce the experimental effort in time-kill curve experiments and was utilized to suggest the experimental design for identification and estimation of an interaction between antibiotics.

OD methods to handle inter occasion variability (IOV) in optimization of individual PK parameter estimates were proposed. The strategy was applied in the design of a sparse sampling schedule that aim to estimate individual exposures of colistin in a multi-centre clinical study. Plasma concentration samples from the first 100 patients have been analysed and indicate that the performance of the design is close to the predicted.

The methods described in this thesis holds promise to facilitate the development of new antibiotics and to improve the use of existing antibiotics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 85
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 206
Keywords
pharmacometric, optimal design, pharmacokinetics, pharmacodynamics, PKPD, resistance, antibiotics, modeling, time-kill curve, colistin, meropenem, ciprofloxacin, non-linear mixed effects models, bayesian
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-264798 (URN)978-91-554-9381-3 (ISBN)
Public defence
2015-12-04, B22, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2015-11-11 Created: 2015-10-19 Last updated: 2015-11-13
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3166-9981

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