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Study Design and Dose Regimen Evaluation of Antibiotics based on Pharmacokinetic and Pharmacodynamic Modelling
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)ORCID iD: 0000-0003-3166-9981
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. , 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 206
Keyword [en]
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: urn:nbn:se:uu:diva-264798ISBN: 978-91-554-9381-3 (print)OAI: oai:DiVA.org:uu-264798DiVA: diva2:862010
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
List of papers
1. Dynamic Interaction of Colistin and Meropenem on a Wild-type and a Resistant strain of Pseudomonas aeruginosa as Quantified in a PKPD-Model
Open this publication in new window or tab >>Dynamic Interaction of Colistin and Meropenem on a Wild-type and a Resistant strain of Pseudomonas aeruginosa as Quantified in a PKPD-Model
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(English)Article in journal (Refereed) Submitted
Keyword
eer r Antibiotic resistance, Antibiotic therapy, Antimicrobial interactions, Pharmacodynamics, PK/PD, Modelling, Pseudomonas aeruginosa, Colistin, Combination treatment, Meropenem
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-264797 (URN)
Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2015-11-13
2. Simulation-based evaluation of PK/PD indices for meropenem across patient groups and experimental designs
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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(English)Article in journal (Refereed) Submitted
Keyword
Antibiotic, Dose selection, Meropenem, Pseudomonas aeruginosa, Pharmacometric
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-264793 (URN)
Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2015-11-13
3. Optimal design of ciprofloxacin in vitro time-kill experiments
Open this publication in new window or tab >>Optimal design of ciprofloxacin in vitro time-kill experiments
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(English)Manuscript (preprint) (Other academic)
Keyword
Optimal design (OD), Time-kill curve, Antibiotic, Ciprofloxacin, PKPD-modeling
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-264794 (URN)
Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2015-11-13
4. A PKPD model characterizing the combined effects of colistin and ciprofloxacin on MG1655 wild type and a clinical isolate of E. coli
Open this publication in new window or tab >>A PKPD model characterizing the combined effects of colistin and ciprofloxacin on MG1655 wild type and a clinical isolate of E. coli
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-264795 (URN)
Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2016-05-12
5. Handling of Inter Occasion Variability (IOV) in Individual Optimal Design (OD) of a Colistin PK Sampling Schedule
Open this publication in new window or tab >>Handling of Inter Occasion Variability (IOV) in Individual Optimal Design (OD) of a Colistin PK Sampling Schedule
2013 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 40, no S1, S123-S124 p.Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-219423 (URN)000330126000132 ()
Conference
The American Conference on Pharmacometrics, May 12-15, 2013, Fort Lauderdale, USA
Available from: 2014-03-09 Created: 2014-02-28 Last updated: 2017-12-05Bibliographically approved
6. A sparse sampling design, with interim evaluation, for estimation of individual colistin pharmacokinetics
Open this publication in new window or tab >>A sparse sampling design, with interim evaluation, for estimation of individual colistin pharmacokinetics
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-264796 (URN)
Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2015-11-13

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