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Title: Development and dose rationale for drug combinations for the treatment of tuberculosis
Author: Muliaditan, Morris
ISNI:       0000 0004 7660 7212
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Better, short treatment options are urgently needed for tuberculosis (TB). To meet this need, drug development in TB requires the use of new integrated methods to ensure the transition of suitable drugs and drug combinations into clinical development, which may ultimately lead to shortening of treatment duration. Despite the ongoing evaluation of new agents in preclinical stages of research, the translation of drug effects to humans along with the corresponding regimens remains empirical, in that novel regimens are progressed without consideration of target exposure or the underlying pharmacokinetic-pharmacodynamic relationships. Hence, one of most critical questions in drug development regards the rationale for the selection of dose and drug combinations. In the first part of this investigation, pharmacokinetic properties of common antitubercular drugs in mice were characterized, followed by an assessment of the utility of plasma concentrations as surrogate for lung tissue exposure. In the second section, data arising from various in vivo experiments were integrated into a drug-disease modelling framework to assess the impact of differences in disease properties on treatment response and disentangle the effect of variability in exposure from variability in pharmacodynamics. Drug combinations were evaluated based on the relative change in the potency of the backbone drug upon addition of the companion drugs. Scaling for interspecies differences in drug- and system-specific properties was found to be necessary for adequate translation of treatment response from mice to patients. Finally, clinical trial simulations were used to optimize the dose rationale of commonly used antitubercular drugs, taking into account the effect of clinical and demographic patient characteristics on drug exposure. It can be anticipated that the use of a semi-mechanistic approach as presented in this thesis can form the basis for translation of drug effect from preclinical species to patients, providing a scientifically more robust rationale for selection of dose and drug combinations in TB.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available