Running title: Population pharmacokinetics of rifampin in patients

2 This article describes the population pharmacokinetics of rifampin in South African pulmonary tuberculosis patients. Three datasets containing 2913 rifampin plasma concentration-time data points, collected from 261 South African pulmonary tuberculosis patients aged 18-72 years and weighing 28.5-85.5 kg, and receiving regular daily treatment including rifampin (450-600 mg) for at least 10 days, were pooled. A compartmental pharmacokinetic model was developed using nonlinear mixed-effects modeling. Variability in the shape of the absorption curve was described using a flexible transit compartment model, in which a delay in the onset of absorption and a gradually changing absorption rate were modeled as the passage of drug through a chain of hypothetical compartments, ultimately reaching the absorption compartment. A previously-described implementation was extended to allow its application to multiple-dosing data. The typical population estimate of oral clearance was 19.2 L·h-1, while volume of distribution was estimated to be 53.2 L. Interindividual variability was estimated to be 52.8 % for clearance and 43.4 % for volume of distribution