Population pharmacokinetics of prothionamide in Korean tuberculosis patients
Joomi Lee1,2, Sung Min Park1,2, Sook-Jin Seong1,2, Jong Gwang Park1,Jeong Ju Seo1,2, Mi-Ri Gwon1,2, Hae Won Lee1, Young-Ran Yoon1,2
1 Clinical Trial Center, Kyungpook National University Hospital, Daegu, Korea. 2 Department of Biomedical Science, Kyungpook National University Graduate School, Daegu, Korea
Objectives: Prothionamide (PTH) is a thioamide drug that has been used for multidrug-resistant tuberculosis (MDR-TB). It is bactericidal and is prescribed as second-line anti-TB medications. The population pharmacokinetic (PK) modeling of PTH has not been developed. The aim of this study was to investigate the population PK of PTH in Korean patients with MDR-TB.
Methods: Seventeen Korean patients with MDR-TB participated in this study. All patients had received multiple oral doses of PTH for at least 2 weeks, with other second-line anti-TB drugs. Plasma samples were collected before and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours after dosing. The concentration of plasma PTH was analyzed with high performance liquid chromatography. The population PK data were analyzed using NONMEM (Ver. 6.2).
Results: A 1-compartment model with Weibull-type absorption described the best fit to a total 221 concentrations of PTH from TB patients. The major population parameter estimates were as follows; ka, 0.509 h-1; Vc (volume of central compartment), 104 L; and CL, 34 L/h. The 1-compartment structural model was validated through visual predictive check (VPC) with no serious model misspecification.
Conclusions: A population PK model was developed and reasonable parameters were obtained from the data of Korean pulmonary TB patients. Further study will be required to develop a final PK model through comparison with other compartment PK models and to evaluate the usefulness of dose-response relationship using bootstrap simulation.
References:
[1] Lee HW, Kim DW, Park JH, et al. Pharmacokinetics of prothionamide in patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2009; 13(9):1161-6.
[2] Abduljalil K, Kinzig M, Bulitta J, et al. Modeling the autoinhibition of clarithromycin metabolism druing repeated oral administration. Antimicrob Agents Chemother. 2009; 53(7):2892-901.
(This study was supported by grants from the Korea Health 21 R&D Project (A070001) & the National Project for Personalized Genomic Medicine (A111218-PG02), Ministry of Health & Welfare, Republic of Korea, by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0022996), Republic of Korea, and by the Pfizer Modeling & Simulation Education Center in Korea (PMECK).)