PI-056 - ALTERNATIVE DOSING GUIDELINES TO IMPROVE OUTCOMES IN MULTIDRUG-RESISTANT TUBERCULOSIS.

T. Chung¹, R. Miyakawa², M. Shin¹, R. Savic^3,4; ¹University of California San Francisco, San Francisco, CA, United States, ²Weill Cornell Medicine, Department of Pediatrics, Weill Cornell Medicine, Department of Pediatrics, NY, US, ³University of California, San Francisco, San Francisco, CA, United States, ⁴UCSF Center for Tuberculosis, University of California, San Francisco, San Francisco, CA, United States.

Background: Malnourished and young children are particularly vulnerable to severe form of tuberculosis (TB) and may have inadequate treatment response treatment. The World Health Organization (WHO) dosing guidelines for second-line TB drugs are based solely only on body weight, which could lead to systematic underdosing and suboptimal outcomes. Therefore, dosing guideline adjustments may be needed, incorporating age and nutritional status. The objectives of this study were to assess and quantify the proportion of patients reaching target drug exposures based on WHO guidelines and to compare this with a proposed method incorporating age and nutrition into dosing for Levofloxacin (LFX) or Linezolid (LZD), group A medications for multidrug-resistant TB, using real-world demographic data from high TB burden countries.

Methods: We simulated the exposure to LFX and LZD following current WHO dosing guidelines using real-world demographic data (e.g., sex, age, body weight, and height) from 30 countries and population pharmacokinetic (PK) models derived from individual participate data meta-analysis. Non-dispersible WHO-recommended formulations (250 and 600 mg for LFX and LZD, respectively) were used for simulation. To this end, a Monte-Carlo simulation dataset was developed that contained 50,000 patient per country. Next, the simulated exposures were compared to target exposures of LFX and LZD, i.e., 101 and 110 mgh/L, respectively, to estimate the proportion of patients reaching target exposures.

Results: A total of 420,773 demographic data from 30 countries was contained in the dataset, of which 51.2 % were male. When following WHO guidelines, we estimated that 74.8 and 62.0 % of MDR patients younger than 5 years who received LFX and LZD, respectively, reached the target drug exposures (Figure 1). Subtherapeutic exposures were most common among malnourished children compared to healthy children. The dosing method incorporating age and nutritional status improved the estimated proportion of target attainment by 6.5 % point for LFX and 13.4 % point for LZD, with a greater % point changes observed among malnourished children.

Conclusion: Our work showed that a simple adjustment in dosing method could be used to improve TB treatment outcomes in children, particularly malnourished children who are at high risk of mortality.