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Novel Pharmacometric Methods for Informed Tuberculosis Drug Development
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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 [en]
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: urn:nbn:se:uu:diva-303872ISBN: 978-91-554-9718-7OAI: oai:DiVA.org:uu-303872DiVA: diva2:1033740
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
List of papers
1. 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
Open this publication in new window or tab >>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
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.

Keyword
Pharmacometrics, Pulmonary distribution, Bronchoalveolar lavage, Epithelial lining fluid, Alveolar cells
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-248443 (URN)10.1007/s00228-014-1798-3 (DOI)000349963800006 ()25620089 (PubMedID)
Available from: 2015-04-02 Created: 2015-03-30 Last updated: 2016-10-09Bibliographically approved
2. Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution
Open this publication in new window or tab >>Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution
2015 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 42, no 6, 699-708 p.Article in journal (Refereed) Published
Abstract [en]

Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid a parts per thousand yen LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

Keyword
Bronchoalveolar lavage, Pulmonary distribution, Sampling design, Pharmacometrics
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-268392 (URN)10.1007/s10928-015-9438-9 (DOI)000363982800007 ()26316105 (PubMedID)
Funder
Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme, 115337
Available from: 2015-12-09 Created: 2015-12-04 Last updated: 2016-10-09Bibliographically approved
3. A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro
Open this publication in new window or tab >>A multistate tuberculosis pharmacometric model: a framework for studying anti-tubercular drug effects in vitro
Show others...
2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 4, 964-974 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Mycobacterium tuberculosis can exist in different states in vitro, which can be denoted as fast multiplying, slow multiplying and non-multiplying. Characterizing the natural growth of M. tuberculosis could provide a framework for accurate characterization of drug effects on the different bacterial states.

METHODS: The natural growth data of M. tuberculosis H37Rv used in this study consisted of viability defined as cfu versus time based on data from an in vitro hypoxia system. External validation of the natural growth model was conducted using data representing the rate of incorporation of radiolabelled methionine into proteins by the bacteria. Rifampicin time-kill curves from log-phase (0.25-16 mg/L) and stationary-phase (0.5-64 mg/L) cultures were used to assess the model's ability to describe drug effects by evaluating different linear and non-linear exposure-response relationships.

RESULTS: The final pharmacometric model consisted of a three-compartment differential equation system representing fast-, slow- and non-multiplying bacteria. Model predictions correlated well with the external data (R(2) = 0.98). The rifampicin effects on log-phase and stationary-phase cultures were separately and simultaneously described by including the drug effect on the different bacterial states. The predicted reduction in log10 cfu after 14 days and at 0.5 mg/L was 2.2 and 0.8 in the log-phase and stationary-phase systems, respectively.

CONCLUSIONS: The model provides predictions of the change in bacterial numbers for the different bacterial states with and without drug effect and could thus be used as a framework for studying anti-tubercular drug effects in vitro.

National Category
Pharmaceutical Sciences Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-273316 (URN)10.1093/jac/dkv416 (DOI)000374232500018 ()26702921 (PubMedID)
Funder
Swedish Research Council, 521-2011-3442EU, FP7, Seventh Framework Programme, 115337
Available from: 2016-01-15 Created: 2016-01-15 Last updated: 2016-10-09Bibliographically approved
4. A model informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions in early tuberculosis drug development
Open this publication in new window or tab >>A model informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions in early tuberculosis drug development
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Tuberculosis treatment involves the use of multiple drugs and therefore there is a risk of not only pharmacokinetic interactions but also pharmacodynamic interactions. From many perspectives identification of pharmacodynamic interactions is not reasonable to carry out in a clinical setting. Thus, the aim of this work was to develop a model-informed pre-clinical approach for identification of exposure-response and pharmacodynamic interactions of drug combinations in order to inform early anti-tuberculosis drug development. In vitro time-kill experiments were performed with Mycobacterium tuberculosis using rifampicin, isoniazid or ethambutol alone as well as in different combinations at clinically relevant concentrations. The Multistate Tuberculosis Pharmacometric model was used to characterize the natural growth and exposure-response relationships of each drug after mono-exposure. Pharmacodynamic interactions during combination exposure were characterized using the General Pharmacodynamic Interaction model with successful separation of each drug’s effect on the potency (EC50) of the other drugs. The approach outlined in this work constitutes groundwork for model informed input to the development of new and enhancement of existing anti-tuberculosis combination regimens.

Keyword
tuberculosis, pharmacodynamic interactions, multistate tuberculosis pharmacometric model, general pharmacodynamic interaction model, isoniazid, rifampicin, ethambutol
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-303870 (URN)
Available from: 2016-10-03 Created: 2016-09-26 Last updated: 2016-10-09

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