UCSF

Since the invention of the microscope and the discovery of microorganisms, mankind has had a huge fascination with microbes – those that live inside us and around us. Despite not being seen by the naked eye, microbes can profoundly affect us in good ways e.g. gut microbes modulating host immunity, bad ways e.g. bacterial infections and curious ways e.g. how the gut microbiome can alter how we process drugs. To tackle such a broad range of issues, this thesis is thus split into two parts. Part 1 will focus on the use of PK-PD models in the context of drug development for infectious airborne microbiome mycobacterium tuberculosis (Mtb). Part 2 takes a different turn into the inside of the human body and will explore how the gut microbiome affects drug disposition.

Part 1: A translational PK-PD toolkit using preclinical in vitro and in vivo data to inform clinical outcomesTuberculosis (TB) is once again the leading cause of death among infectious diseases as of 2022. This happens despite known cures, due to the long and complex 6 month regimen with good adherence required for TB treatment. There is thus a pressing need for new drugs and drug treatments that will shorten TB treatment. While multiple new drugs have been developed, and thus many new possibilities for novel drug regimens, drug development is expensive and only a fraction of these drugs and drug regimens can be used for testing. Using a translational PK-PD tool kit, we aim to make use of preclinical in vitro and in vivo data which is much less resource intensive, to predict and prioritize regimens prior to resource-intensive clinical trials.

Part 2: How the microbiome influences drug dispositionDrug clearance is highly dependent on CYP abundance and activity. However, significant interindividual variation in major liver enzyme CYP3A of up to 30- to 40-fold variation exists. Genetic polymorphisms alone cannot account for this variation. Recent evidence suggests the gut microbiome can modulate CYP expression and activity. Here, we aim to elucidate the functional consequences and mechanisms of the gut microbiome's modulation of CYP3A4 activity.