## 1 Introduction  
Drug discovery and development is a challenging, lengthy, and costly process. The costs of a novel drug reaching the market can be as much as 2-3 billion dollars [1]. In the early discovery phase, libraries consisting of thousands of compounds can be synthesized chemically and tested for efficacy _in vitro_ at a relatively low cost. The largest expenditures are in the late preclinical and clinical phases of drug development, where the efficacy and safety of treatment are assessed. Smart decisions need to be made regarding which compounds and regimens should progress through the preclinical phase and subsequently into clinical trials. Early characterization of each compound's exposure-response relationship, i.e., pharmacokinetic (PK)-pharmacodynamic (PD) relationship and potential interactions within regimens and with commonly co-administered drugs, can allow for informative decision making throughout preclinical development and into clinical development [2]. Tuberculosis (TB) is the leading cause of adult mortality through infectious diseases and 10 million new cases are reported globally every year [3]. Sensitive TB is currently treated with a six-month regimen of antibiotics, consisting of isoniaizd, pyrazinamide, rifampicin and ethambutol, which was developed in the mid-twentieth century. This therapy is believed to be suboptimal and was not developed using modern approaches for drug development, thereby lacking important information on the PK-PD relationship. Therefore, clinical trials have recently been conducted in order to define the relationship between exposure and efficacy, as well as safety, where statistically significant exposure-response relationships for rifampicin have been identified, in order to support a higher dose of rifampicin [4; 5; 6; 7]. Almost one in five patients will acquire multidrug-resistant tuberculosis (MDR-TB) or rifampicin-resistant tuberculosis (RR-TB) [3]. Recently, the new anti-TB drugs bedaquiline, delamamid and pretomandi were conditionally approved against MDR-TB, which led to updates to the World Health Organization (WHO) treatment guideline for MDR-TB [8]. Bedaquiline is a diarylquinoline, a new class of antibiotics. It is an inhibitor of the membrane-bound adenosine triphosphate (ATP)-syntase enzyme, therefore blocking mycobacterial ATP formation and energy metabolism. Bedaquiline is therefore bactericidal for dormant mycobacteria as well, a preferable feature for the shortening of treatment duration and prevention of relapse [9]. Delamandi is a nitroimidazole and affects the mycobacterial cell wall, thereby also improving drug penetration into the mycobacterium. It is the most potent TB drug and is active against replicating and dormant mycobacteria as well [9]. The combination of delamamid with bedaquiline is, however, not recommended, due to QT-prolongation-related cardiotoxicity [10]. Pretomandi belongs to the same class of antibiotics as delamamid [9]. Pretomandi was developed as part of a drug combination together with bedaquiline and linezold, an oxazolidinone-class otherwise used for the treatment of pneumonia and skin infection. There is a clear need for the additional development of new effective drug combinations. The European Medical Agency (EMA) drug development guideline for TB specifies that efforts should be made to develop entirely new regimens to treat TB, rather than focusing on single drugs [11]. Due to the burden of polypharmacy for the patients and the increased risk of side effects, the focus should be on developing new regimens instead of the development of single agents as an add-on to a current regimen which was recommended in the earlier EMA TB drug development guideline [12]. Of the three new drugs against TB, only pretomandi is approved as a new combination regimen, while bedaquiline and delamamid were developed as add-ons to existing therapy [13].