Tuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the... Show moreTuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the effectiveness and safety of treatments against TB. This PhD thesis has described how various quantitative pharmacology modeling approaches can contribute to the further development and optimization of both existing and novel therapies and treatment strategies against TB. Show less
Mehta, K.; Guo T.; Graaf, P.H. van der, Hasselt, J.G.C. van 2023
AIM\nMETHODS\nRESULTS\nCONCLUSION\nBedaquiline, pretomanid, and linezolid combination (BPaL) treatment against Mycobacterium tuberculosis is promising yet safety and adherence concerns exist that... Show moreAIM\nMETHODS\nRESULTS\nCONCLUSION\nBedaquiline, pretomanid, and linezolid combination (BPaL) treatment against Mycobacterium tuberculosis is promising yet safety and adherence concerns exist that motivates exploration of alternative dosing regimens. We developed a mechanistic modeling framework to compare the efficacy of the current and alternative BPaL treatment strategies.\nPharmacodynamic models for each drug in the BPaL combination treatment were developed using in vitro time-kill data. These models were combined with pharmacokinetic models, incorporating bodyweight, lesion volume, site-of-action distribution, bacterial susceptibility, and pharmacodynamic interactions to assemble the framework. The model was qualified by comparing the simulations against the observed clinical data. Simulations were performed evaluating bedaquiline and linezolid approved (bedaquiline 400mg once daily (QD) 14-days followed by 200mg three times a week, linezolid 1200mg QD) and alternative dosing regimens (bedaquiline 200mg QD, linezolid 600mg QD).\nThe framework adequately described the observed anti-bacterial activity data in patients following monotherapy for each drug and approved BPaL dosing. The simulations suggested a minor difference in median time to colony forming units (CFU)-clearance state with the bedaquiline alternative compared to the approved dosing and the linezolid alternative compared to the approved dosing. Median time to non-replicating-clearance state was predicted to be 15-days from the CFU-clearance state.\nThe model-based simulations suggested that comparable efficacy can be achieved using alternative bedaquiline and linezolid dosing, which may improve safety and adherence in drug-resistant tuberculosis patients. The framework can be utilized to evaluate treatment optimization approaches, including dosing regimen and duration of treatment predictions to eradicate both replicating- and non-replicating bacteria from lung and lesions. Show less
Mehta, K.; Spaink, H.P.; Ottenhoff, T.H.M.; Graaf, P.H. van der; Hasselt, J.G.C. van 2022
Host-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB)... Show moreHost-directed therapies (HDTs) that modulate host-pathogen interactions offer an innovative strategy to combat Mycobacterium tuberculosis (Mtb) infections. When combined with tuberculosis (TB) antibiotics, HDTs could contribute to improving treatment outcomes, reducing treatment duration, and preventing resistance development. Translation of the interplay of host-pathogen interactions leveraged by HDTs towards therapeutic outcomes in patients is challenging. Quantitative understanding of the multifaceted nature of the host-pathogen interactions is vital to rationally design HDT strategies. Here, we (i) provide an overview of key Mtb host-pathogen interactions as basis for HDT strategies; and (ii) discuss the components and utility of quantitative systems pharmacology (QSP) models to inform HDT strategies. QSP models can be used to identify and optimize treatment targets, to facilitate preclinical to human translation, and to design combination treatment strategies. Show less
