Pharmacokinetic, efficacy and safety modeling of new treatments against drug-resistant tuberculosis

Tuberculosis (TB) is an ancient infectious disease that remains one of the greatest killers on the planet. Its eradication is impeded by the development of resistance to first-line treatment. Each year half a million patients are infected with drug-resistant (DR) TB. Of those, only 1 in 3 patients are started on treatment, and only half of the patients accessing treatment have a successful outcome. Fortunately, during the last decade, new drugs have been registered for treatment of DR-TB, such as bedaquiline and delamanid. The aim of this thesis was to develop pharmacometric models to assess the benefits and risks of these new drugs, as part of multidrug therapies. Regarding pharmacokinetic (PK), a population PK model of delamanid and its metabolite DM-6705 was developed and absence of PK drug interaction with bedaquiline and dolutegravir was confirmed. Regarding efficacy, a previously established relationship where bedaquiline exposures impact the half-life of the decline of the mycobacterial load in patients was validated with data from a more-difficult to treat population. Regarding safety, firstly, the profile of bedaquiline toxicity was characterized by evaluating the time course of heart QTcF interval and hepatic enzymes levels. While bedaquiline’s metabolite concentrations were found to be responsible for the drug-related QTcF increase (in a model accounting for circadian rhythm patterns, time on study, effect of concomitant medication with QT liability, and patient demographics), no relationship could be detected between drug exposure and transaminase levels. Secondly, delamanid’s metabolite (and not delamanid) was found to play a significant role in QTcF prolongation. Lastly, in patients receiving both bedaquiline and delamanid, the pharmacodynamic drug interaction on QTcF interval was assessed and indicated no higher risk of safety events under the combination. All in all, the developed models were able to predict the PK, efficacy and safety profiles of bedaquiline and/or delamanid, with a once daily dosing regimen, and supported the use of this novel regimen, more convenient both for patients and drug providers. In summary, the pharmacometric approaches presented provide a quantitative understanding of desired and undesired effects of new treatments against DR-TB, and may help to define optimized anti-TB dosing regimens