Development and dose rationale for drug combinations for the treatment of tuberculosis

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

The Metaphysical Orientation towards the Other as the Foundation of the Political Idea of Community

Cilj je rada razmotriti važnost metafizike za pitanja dobra i prijateljstva kao preduvjeta društvenoga i političkoga zajedništva. Vidljivo je da je danas ideja prijateljstva ozbiljno narušena interesnim i egoističnim postulatima utemeljenima na materijalnoj egzistenciji, stoga je potrebno pitanje o egzistenciji postaviti u njezine metafizičke okvire okrenutosti prema drugomu, što je temeljni supstrat kršćanske metafizike oslonjene na Platonove i Aristotelove postulate. Rad će se usredotočiti na Platonove, Aristotelove, Augustinove i Tomine uvide kojima se otvara mogućnost mišljenja Drugoga kao preduvjeta filozofije i politike prijateljstva. Cilj je rada samo naznačiti neke odnose koji spajaju metafizičke i političke uvide o važnosti ideje dobra i prijateljstva kao preduvjeta otvorenosti prema drugima i time mogućnosti ostvarenja bilo kakvoga oblika zajedništva.The aim of this paper is to discuss the importance of metaphysics for the questions of good and friendship as preconditions for the social and political community. It is obvious that the idea of friendship today is seriously impaired by interest and egoistic postulates based on material existence, therefore, it is necessary to put the question on existence into its metaphysical frameworks of orientation towards the Other, which is the fundamental substratum of Christian metaphysics based on Plato’s and Aristotle’s postulates. The paper will focus on Plato’s, Aristotle’s, Augustine’s and Thomas’ insights which open up the possibility of thinking of the Other as a precondition of a philosophy and politics of friendship. The aim of the paper is only to indicate some relationships that connect the metaphysical and political insights about the importance of the idea of good and friendship as a precondition of openness to others and thus the possibility of achieving any form of community

First-time-in-human study and prediction of early bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0–τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0–14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.

Application of quantitative protein mass spectrometric data in the early predictive analysis of membrane-bound target engagement by monoclonal antibodies

ABSTRACTModel-informed drug discovery advocates the use of mathematical modeling and simulation for improved efficacy in drug discovery. In the case of monoclonal antibodies (mAbs) against cell membrane antigens, this requires quantitative insight into the target tissue concentration levels. Protein mass spectrometry data are often available but the values are expressed in relative, rather than in molar concentration units that are easier to incorporate into pharmacokinetic models. Here, we present an empirical correlation that converts the parts per million (ppm) concentrations in the PaxDb database to their molar equivalents that are more suitable for pharmacokinetic modeling. We evaluate the insight afforded to target tissue distribution by analyzing the likely tumor-targeting accuracy of mAbs recognizing either epidermal growth factor receptor or its homolog HER2. Surprisingly, the predicted tissue concentrations of both these targets exceed the Kd values of their respective therapeutic mAbs. Physiologically based pharmacokinetic (PBPK) modeling indicates that in these conditions only about 0.05% of the dosed mAb is likely to reach the solid tumor target cells. The rest of the dose is eliminated in healthy tissues via both nonspecific and target-mediated processes. The presented approach allows evaluation of the interplay between the target expression level in different tissues that determines the overall pharmacokinetic properties of the drug and the fraction that reaches the cells of interest. This methodology can help to evaluate the efficacy and safety properties of novel drugs, especially if the off-target cell degradation has cytotoxic outcomes, as in the case of antibody-drug conjugates