The current dosing regimen of pyrazinamide for tuberculosis is based on body weight derived from concerns at higher doses. The largest pyrazinamide exposure-response and safety analysis was performed and showed that weight was not a clinically significant predictor of clearance, suggesting the validity of a 1,000 mg flat dose. However, according to the analysis, the bioavailability of pyrazinamide was affected by dose levels preventing a clear evaluation of the weight effect on clearance which is influenced by bioavailability. Therefore, we aimed to demonstrate the effect of weight on pyrazinamide pharmacokinetics (PK) using flat dosing data excluding the dose effect and to strengthen the dosing strategy for adults with tuberculosis.Methods: Data from three phase 2 clinical trials (NC-002, NC-005, and SimpliciTB) and one phase 3 clinical trial (STAND) were used to develop the population PK modeling. Population PK modeling was performed using NONMEM and linear, power, and piecewise linear relationship were explored to explain the weight effect on PK parameters. We compared the proportion of participants within therapeutic window across the current weight-based and flat dosing strategies.Results: A total of 820 participants with 1500 mg flat dose were included. The PK of pyrazinamide was appropriately explained by a one-compartment model, first-order absorption with lag time, and first-order elimination. The effect of weight on clearance and volume of distribution was best described by a linear relationship, indicating that the clearance increases by approximately 11% for every 10 kg increase in body weight. The flat dosing of pyrazinamide with 1,000 mg achieved 55% of participants within the therapeutic window while current weight-based dosing achieved 12%.Conclusions: This analysis indicated that the effect of weight on pyrazinamide PK was not significant factor to justify weight-based dosing and a flat dosing of pyrazinamide with 1,000 mg once-daily would be appropriate.