Model-informed precision pyrazinamide dosing: The establishment of a population pharmacokinetic model repository for...

Pyrazinamide (PZA) plays an important role in the treatment of tuberculosis (TB) and adequate PZA exposure is necessary to achieve optimal treatment outcomes. However, its pharmacokinetics exhibit marked interindividual variability. Such variability undermines the 'one-dose-fits-all' paradigm. Our work directly addresses this therapeutic dilemma by advancing model-informed precision dosing (MIPD) through systematic population pharmacokinetic (PPK) model evaluation.

We conducted a comprehensive search of PubMed, Embase, and Web of Science to identify published PPK models and collected information on the study design, patient demographics, and final parameter estimates of these models. Based on the collected information, we used MIPD approach to establish a PZA PPK model repository and developed a web-based dashboard using R-shiny to visualize the concentration-time profile, investigate the impact of covariates on pharmacokinetic (PK), and estimate patient probability of target attainment (PTA) for a predefined dosing regimen.

Sixteen studies conducted in adults and five studies conducted in paediatric patients were included in this model repository. Body size was identified as the most important covariate affecting the clearance of PZA. HIV/TB co-infection and pregnancy did not cause a significant change in PZA exposure; thus, no dosage adjustment was required. Moreover, to achieve the target exposure, the dosage per body weight was higher in paediatric and elderly patients with diabetes than in adults (40 mg/kg/24 h and 23 mg/kg/24 h for younger children and adults, respectively).

The developed model repository and dashboard have a broad range of potential applications in the MIPD of PZA.