title: Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.
abstract: Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.).
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Sang-In
authors.initials: SI
authors.lastname: Park
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Jaeseong
authors.initials: J
authors.lastname: Oh
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Jang
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Jangsoo
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Seol Ju
authors.initials: SJ
authors.lastname: Moon
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea.
authors.forename: Jong Sun
authors.initials: JS
authors.lastname: Park
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea.
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea.
authors.forename: Junghan
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Republic of Korea jychung@snubh.org.
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Chung
mesh_terms: D000328:Adult; D010131:Aminosalicylic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003523:Cycloserine / Q000008:administration & dosage / Q000493:pharmacokinetics; D016903:Drug Monitoring / Q000379:methods; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000493:pharmacokinetics; D064368:Healthy Volunteers; D006801:Humans; D007612:Kanamycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D064704:Levofloxacin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D000077266:Moxifloxacin; D011515:Prothionamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D011718:Pyrazinamide / Q000008:administration & dosage / Q000493:pharmacokinetics; D013307:Streptomycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D007612:Kanamycin; D010131:Aminosalicylic Acid; D064704:Levofloxacin; D011515:Prothionamide; D003523:Cycloserine; D000077266:Moxifloxacin; D013307:Streptomycin