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A pharmacometric pulmonary model predicting the extent and rate of distribution from plasma to epithelial lining fluid and alveolar cells-using rifampicin as an example
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2015 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 3, 313-319 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of the study was to develop a drug-unspecific approach to pharmacometric modeling for predicting the rate and extent of distribution from plasma to epithelial lining fluid (ELF) and alveolar cells (AC) for data emanating from studies involving bronchoalveolar lavage (BAL) sampling, using rifampicin (RIF) as an example. Data consisting of RIF plasma concentrations sampled at approximately 2 and 4 h postdose and ELF and AC concentrations quantified from one BAL sample, taken at approximately 4 h postdose, in 40 adult subjects without tuberculosis was used as an example for model development. This study emphasized the usage of drug-specific plasma pharmacokinetics (PK) for a correct characterization of plasma to pulmonary distribution. As such, RIF PK was described using absorption transit compartments and a one compartment distribution model coupled with an enzyme turn-over model. The ELF and AC distribution model consisted of characterization of the rate of distribution of drug from plasma to ELF and AC by two distribution rate constant, k (ELF) and k (AC), respectively. The extent of distribution to ELF and AC was described by unbound ELF/plasma concentration ratio (R (ELF/unbound-plasma)) and unbound AC/plasma concentration ratio (R (AC/unbound-plasma)) which typical values were predicted to be 1.28 and 5.5, respectively. The model together with a drug-specific plasma PK description provides a tool for handling data from both single and multiple BAL sampling designs and directly predicts the rate and extent of distribution from plasma to ELF and AC. The model can be further used to investigate design aspects of optimized BAL studies.

Place, publisher, year, edition, pages
2015. Vol. 71, no 3, 313-319 p.
Keyword [en]
Pharmacometrics, Pulmonary distribution, Bronchoalveolar lavage, Epithelial lining fluid, Alveolar cells
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-248443DOI: 10.1007/s00228-014-1798-3ISI: 000349963800006PubMedID: 25620089OAI: oai:DiVA.org:uu-248443DiVA: diva2:800290
Available from: 2015-04-02 Created: 2015-03-30 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Novel Pharmacometric Methods for Informed Tuberculosis Drug Development
Open this publication in new window or tab >>Novel Pharmacometric Methods for Informed Tuberculosis Drug Development
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With approximately nine million new cases and the attributable cause of death of an estimated two millions people every year there is an urgent need for new and effective drugs and treatment regimens targeting tuberculosis. The tuberculosis drug development pathway is however not ideal, containing non-predictive model systems and unanswered questions that may increase the risk of failure during late-phase drug development. The aim of this thesis was hence to develop pharmacometric tools in order to optimize the development of new anti-tuberculosis drugs and treatment regimens.

The General Pulmonary Distribution model was developed allowing for prediction of both rate and extent of distribution from plasma to pulmonary tissue. A distribution characterization that is of high importance as most current used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic properties influencing drug distribution to the site of action. The developed optimized bronchoalveolar lavage sampling design provides a simplistic but informative approach to gathering of the data needed to allow for a model based characterization of both rate and extent of pulmonary distribution using as little as one sample per subject. The developed Multistate Tuberculosis Pharmacometric model provides predictions over time for a fast-, slow- and non-multiplying bacterial state with and without drug effect. The Multistate Tuberculosis Pharmacometric model was further used to quantify the in vitro growth of different strains of Mycobacterium tuberculosis and the exposure-response relationships of three first line anti-tuberculosis drugs. The General Pharmacodynamic Interaction model was successfully used to characterize the pharmacodynamic interactions of three first line anti-tuberculosis drugs, showing the possibility of distinguishing drug A’s interaction with drug B from drug B’s interaction with drug A. The successful separation of all three drugs effect on each other is a necessity for future work focusing on optimizing the selection of anti-tuberculosis combination regimens.

With a focus on pharmacokinetics and pharmacodynamics, the work included in this thesis provides multiple new methods and approaches that individually, but maybe more important the combination of, has the potential to inform development of new but also to provide additional information of the existing anti-tuberculosis drugs and drug regimen.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 222
Keyword
pharmacokinetics, pharmacodynamics, PKPD, pharmacometric, nonlinear mixed-effects models, multistate tuberculosis pharmacometric model, general pharmacodynamic interaction model, general pulmonary distribution model, tuberculosis, rifampicin, isoniazid, ethambutol
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-303872 (URN)978-91-554-9718-7 (ISBN)
Public defence
2016-11-25, B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-11-03 Created: 2016-09-26 Last updated: 2016-11-16

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Clewe, OskarSimonsson, Ulrika S. H.

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