UCSF

Childhood tuberculosis (TB) affects one million children annually, and in 2019, 194,000 children under 15 years of age died from TB. Malnourished, HIV-positive, and young children have an increased risk of TB disease progression, severe forms of TB, and poor treatment outcomes. Historically, children with TB have been treated as small adults. This may contribute to poorer outcomes due to pharmacokinetic differences between adults and children that result in suboptimal drug exposure. The aims of this work were to apply modeling and simulation to optimize pediatric dosing of important drugs/regimens for drug-susceptible TB, drug-resistant TB, and latent TB infection. Current treatment guidelines for drug-susceptible TB endorsed by the World Health Organization (WHO) recommend dosing children by body weight alone, which may lead to systematic underdosing and worse treatment outcomes in underweight children. A systematic review and meta-analysis was performed to assess rifampicin pharmacokinetics in children. At the current WHO recommendations, rifampicin exposures were much lower in children compared to adults. Younger and HIV-positive children trended toward lower exposures compared to older and HIV-negative children, respectively, but data reporting by these groups were too sparse to draw definitive conclusions. In a separate study, an integrated pharmacologic-epidemiologic model was developed to predict childhood TB outcomes in a real-world population of children under 5 years of age from high burden TB countries. An alternative dosing method, which dosed children by ideal body weight instead of actual body weight, was predicted to reduce unfavorable child outcomes by at least 33%, with major improvements in the youngest children and those who were malnourished. The findings from both analyses support higher doses of rifampicin than currently recommended. Moxifloxacin is a high-priority drug for drug-resistant TB treatment per WHO guidelines. However, doses are not optimized for children due to a lack of pharmacokinetic and safety data, especially in young children. To address this need, the population pharmacokinetics and relationship with QT-interval prolongation were characterized in a cohort of 85 children with TB (median age 4.6 years). Optimal moxifloxacin doses were found to be 10-50% higher than current WHO recommendations, depending on child weight. The risk of QT-interval prolongation was low during the study, but requires further assessment at higher doses, especially with coadministration of other QT-prolonging anti-TB agents such as clofazimine and bedaquiline. Tuberculosis disease can be prevented in those with latent infection with anti-tuberculosis therapy. Novel short-course rifapentine-based therapies are an appealing, non-inferior alternative to the standard 9-months of isoniazid. However, rifapentine pharmacokinetic data in children are lacking. To inform on optimal rifapentine dosing in children, the pharmacokinetics and autoinduction profile were first characterized in adults. The adult model informed the model structure for pediatric simulations as well as pharmacokinetic targets for different regimens. Then, optimized and pragmatic weight band dosing was proposed for the 3-month once weekly regimen (3HP) for labelled use and for the experimental regimens being evaluated in pediatric clinical trials. Lastly, prior knowledge of rifapentine (and rifamycins, in general) pharmacokinetics were leveraged to inform the design of a pediatric PK study evaluating daily rifapentine for TB prevention. Collectively, this dissertation research contributes to the prevention and treatment of TB in children by applying model-based approaches to optimize the dosing of key drugs in current and novel regimens. There is a focus on vulnerable child populations that are typically underrepresented in clinical trials and underserved by standard weight-based dosing practices but represent a large burden of the mortality (e.g., malnourished, HIV-coinfected, young).