Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis

Min Jung Chang, Byunghak Jin, Jung woo Chae, Hwi yeol Yun, Eun Sun Kim, Yeon Joo Lee, Young Jae Cho, Ho Il Yoon, Choon Taek Lee, Kyoung Un Park, Junghan Song, Jae Ho Lee, Jong Sun Park

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters. The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500–750 mg of cycloserine QD, 4.95–6.6 g of PAS twice daily and 750–1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.

Original languageEnglish
Pages (from-to)677-687
Number of pages11
JournalInternational Journal of Antimicrobial Agents
Volume49
Issue number6
DOIs
Publication statusPublished - 2017 Jun 1

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Aminosalicylic Acid
Cycloserine
Multidrug-Resistant Tuberculosis
Kanamycin
Pharmacokinetics
Pharmaceutical Preparations
Population
Therapeutics
Weights and Measures
Tandem Mass Spectrometry
Liquid Chromatography
moxifloxacin
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Chang, Min Jung ; Jin, Byunghak ; Chae, Jung woo ; Yun, Hwi yeol ; Kim, Eun Sun ; Lee, Yeon Joo ; Cho, Young Jae ; Yoon, Ho Il ; Lee, Choon Taek ; Park, Kyoung Un ; Song, Junghan ; Lee, Jae Ho ; Park, Jong Sun. / Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis. In: International Journal of Antimicrobial Agents. 2017 ; Vol. 49, No. 6. pp. 677-687.
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abstract = "Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters. The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500–750 mg of cycloserine QD, 4.95–6.6 g of PAS twice daily and 750–1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.",
author = "Chang, {Min Jung} and Byunghak Jin and Chae, {Jung woo} and Yun, {Hwi yeol} and Kim, {Eun Sun} and Lee, {Yeon Joo} and Cho, {Young Jae} and Yoon, {Ho Il} and Lee, {Choon Taek} and Park, {Kyoung Un} and Junghan Song and Lee, {Jae Ho} and Park, {Jong Sun}",
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Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis. / Chang, Min Jung; Jin, Byunghak; Chae, Jung woo; Yun, Hwi yeol; Kim, Eun Sun; Lee, Yeon Joo; Cho, Young Jae; Yoon, Ho Il; Lee, Choon Taek; Park, Kyoung Un; Song, Junghan; Lee, Jae Ho; Park, Jong Sun.

In: International Journal of Antimicrobial Agents, Vol. 49, No. 6, 01.06.2017, p. 677-687.

Research output: Contribution to journalArticle

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T1 - Population pharmacokinetics of moxifloxacin, cycloserine, p-aminosalicylic acid and kanamycin for the treatment of multi-drug-resistant tuberculosis

AU - Chang, Min Jung

AU - Jin, Byunghak

AU - Chae, Jung woo

AU - Yun, Hwi yeol

AU - Kim, Eun Sun

AU - Lee, Yeon Joo

AU - Cho, Young Jae

AU - Yoon, Ho Il

AU - Lee, Choon Taek

AU - Park, Kyoung Un

AU - Song, Junghan

AU - Lee, Jae Ho

AU - Park, Jong Sun

PY - 2017/6/1

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N2 - Control of multi-drug-resistant tuberculosis (MDR-TB) requires extensive, supervised chemotherapy because second-line anti-TB drugs have a narrower therapeutic range than first-line drugs. This study aimed to develop population pharmacokinetic (PK) models for second-line drugs in patients with MDR-TB, evaluate the recommended dosage regimens and, if necessary, suggest new dosage regimens. A prospective, single-centre PK study was performed on second-line anti-TB drugs in patients with MDR-TB. Moxifloxacin, cycloserine, p-aminosalicylic acid (PAS), kanamycin and other second-line drugs were administered to the patients. Plasma concentrations were analysed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Population PK models were developed using non-linear mixed effect modelling (NONMEM, Version 7.30; ICON Development Solutions, Ellicott City, MD, USA). Simulations were performed using the calculated PK parameters. The respective absorption rate constant, apparent clearance and apparent volume of distribution values were as follows: 0.305/h, 9.37 L/h and 56.7 L for moxifloxacin; 0.135/h, 1.38 L/h and 10.5 L for cycloserine; 0.510/h, 30.8 L/h and 79.4 L for PAS; and 1.67/h, 3.75 L/h and 15.2 L for kanamycin. The simulations showed that the following dosage regimens were more likely to be within the recommended concentration ranges than the raw data in this study: 200 mg of moxifloxacin once daily (QD) (patient weight <50 kg) and 400 mg of moxifloxacin QD (patient weight ≥50 kg), 500–750 mg of cycloserine QD, 4.95–6.6 g of PAS twice daily and 750–1000 mg of intramuscular kanamycin QD. These findings indicate that the recommended doses should be revised to improve the clinical outcomes of MDR-TB treatment.

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