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.
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.
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%.
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.
The authors acknowledge the Brewelskloof Hospital authorities for permission to conduct the study; the staff members at Brewelskloof Hospital for their support; the Pharmaceutical Services, Provincial Administration of the Western Cape for supplying anti-tuberculosis tablets; the Department of Health, Province of the Western Cape for permission to conduct the study; and the patients who participated in the study.
Compliance with Ethical Standards
The South African Medical Research Council and the University of the Western Cape financially supported this research project.
Conflict of interest
The authors declare that they have no competing interests.
The study was approved by the ethics committee of the University of the Western Cape (Ref: 07/6/12) and the University of Cape Town (Ref: 777/2014). The principles outlined in the declaration of Helsinki were adhered to when conducting the study.
Informed consent was obtained from all individual participants included in the study.
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