Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis

Background and objectives Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables. Methods This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8, 16 and 24 h after drug administration. Plasma concentrations of pyrazinamide and pyrazinoic acid were analysed using a validated LC-MS/MS method. Nonlinear mixed-effects modelling using Monolix 2018R1 software was employed to estimate population pharmacokinetic parameters. Results A one-compartment pharmacokinetic model with transit compartment absorption process and first-order elimination best described the pyrazinamide and pyrazinoic acid concentration-time data. The estimated population pharmacokinetic parameters were 0.7 h, 3.38 h -1 , 57.1 l, 4.37 L/h and 10.5 L/h for mean transit time, absorption rate constant, apparent distribution volume for pyrazinamide, and apparent clearance for pyrazinamide and pyrazinoic acid (CLm/F), respectively. These parameters were not affected by patient age, HIV status or sex. The parameter variability in CLm/F was the highest (83.5%), while the rest of the parameters ranged from 16.2 to 58%. Conclusions The developed population pharmacokinetic model adequately described the disposition of pyrazinamide and pyrazinoic acid and can be useful for dose determination of pyrazinamide in patients with MDR-TB.