UCSF

Tuberculosis (TB) remains one of the leading infectious causes of death worldwide despite the availability of curative multidrug therapy. Although standardized treatment regimens achieve high overall cure rates, substantial interindividual variability persists in drug exposure, treatment response, toxicity, and relapse risk. Furthermore, repeated failures of several treatment-shortening strategies in phase 3 clinical trials highlight persistent gaps in understanding the pharmacologic and biologic determinants of treatment outcomes. This dissertation investigated pharmacokinetic-pharmacodynamic (PKPD) and host genetic determinants of treatment response in drug-susceptible TB using data from the phase 3 Tuberculosis Trials Consortium (TBTC) Study 31/ACTG A5349 clinical trial.The first objective of this dissertation was to characterize exposure-response relationships for rifampicin, pyrazinamide, and moxifloxacin within contemporary multidrug treatment regimens. Population nonlinear mixed-effects models were developed to characterize drug pharmacokinetics and quantify interindividual variability in systemic exposure. Associations between drug exposure and clinical efficacy and safety outcomes were subsequently evaluated using regression and time-to-event modeling approaches.The rifampicin analyses demonstrated substantial variability in systemic exposure despite standardized dosing. However, rifampicin exposure within the observed range of the standard 600 mg daily dose was not associated with differences in stable culture conversion, tuberculosis-related unfavorable outcomes, or serious adverse events. Pharmacokinetic simulations further demonstrated that flat dosing produced exposure distributions comparable to current weight-banded dosing strategies, supporting the feasibility of simplified rifampicin dosing approaches within standard six-month therapy.The pyrazinamide analyses identified approximately seven-fold variability in systemic exposure among participants receiving standardized therapy. Both efficacy and safety outcomes were associated with pyrazinamide exposure, enabling identification of therapeutic exposure windows associated with favorable benefit-risk profiles. Flat dosing of pyrazinamide at 1000 mg daily was predicted to increase the proportion of participants achieving target exposures compared with current weight-banded dosing approaches. These findings provide clinically relevant evidence supporting future pyrazinamide dose optimization strategies.The moxifloxacin analyses evaluated whether variability in moxifloxacin exposure contributed to outcomes within the four-month rifapentine-moxifloxacin treatment-shortening regimen. Although substantial pharmacokinetic variability was observed and several demographic and clinical covariates influenced exposure, moxifloxacin exposure within the standard 400 mg daily dosing range was not associated with treatment efficacy or major safety outcomes. These findings suggest that variability in moxifloxacin exposure alone does not explain differential outcomes observed in fluoroquinolone-containing treatment-shortening regimens and reinforce the complexity of multidrug regimen performance in TB.The second objective of this dissertation was to investigate host genetic determinants of anti-TB pharmacokinetics and treatment response. Genome-wide and candidate pharmacogenetic analyses identified NAT2 acetylator status as the primary determinant of isoniazid clearance, while variants in AADAC and UGT1A1 influenced rifapentine and moxifloxacin pharmacokinetics, respectively. Importantly, NAT2 genotype differentiated treatment response across rifapentine-containing shortened regimens, with rapid and intermediate acetylators experiencing higher rates of tuberculosis-related unfavorable outcomes compared with slow acetylators. Addition of NAT2 genotype modestly improved prediction of unfavorable outcomes beyond baseline clinical characteristics alone. In contrast, no additional genetic variants demonstrated strong associations with efficacy or severe safety outcomes.Collectively, this dissertation demonstrates that substantial pharmacologic and biologic variability exists among patients receiving standardized tuberculosis therapy and that host pharmacogenetic factors may contribute to differential treatment responses, particularly in treatment-shortening regimens. At the same time, the findings illustrate that exposure-response relationships in multidrug TB therapy are highly complex and may not be fully explained by plasma drug exposure alone. By integrating PKPD and pharmacogenetic analyses within a large phase 3 clinical trial platform, this work advances understanding of the determinants of tuberculosis treatment response and supports future efforts toward individualized dosing strategies, biologically informed treatment optimization, and precision medicine approaches in tuberculosis therapeutics.