Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis

• Type of Material: Article
• Authors: Wael A. Alghamdi, University of Florida; Abdullah Alsultan, King Saud University; Mohammad H. Al-Shaer, University of Florida; Guohua An, University of Iowa; Shahriar Ahmed, International Centre for Diarrhoeal Diseases Research; Yosra Alkabab, University of Virginia; Sayera Banu, International Centre for Diarrhoeal Diseases Research; Ketevan Barbakadze, National Center for TB and Lung Diseases; Eric Houpt, University of Virginia; Maia Kipiani, National Center for TB and Lung Diseases; Lali Mikiashvili, National Center for TB and Lung Diseases; Stephan Schmidt, University of Florida; Scott K. Heysell, University of Virginia; Russell Ryan Kempker, Emory University; J. Peter Cegielski, Emory University; CA Peloquin, University of Florida
• Language: English
• Date: 2019-05-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2019 Alghamdi et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/AAC.00055-19
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• ISSN: 0066-4804
• Volume: 63
• Issue: 5
• Grant/Funding Information: Funding was also provided in part by the Bill and Melinda Gates Foundation via a subaward of grant OPP1031105, awarded to the Critical Path to TB Regimens (CPTR) Initiative at the Critical Path Institute (C-Path).; This work was supported in part by the National Institutes of Health Fogarty International Center (grant D43 TW007124 to R.R.K. and M.K.); the National Institute of Allergy and Infectious Diseases (grant K23 AI103044 to R.R.K. and grant R21 AI122001 to R.R.K., M.K., K.B., and L.M.); the National Institutes of Health (grant U01 AI115594 to S.K.H. and E.R.H. and grant T32 AI007046-41 to Y.A.); and the International Science and Technology Center (grant G-2200 to R.R.K. and M.K.).
• Keywords: target attainment; drug-resistant tuberculosis; DRUGS; MULTIDRUG-RESISTANT TUBERCULOSIS; TERIZIDONE; pharmacodynamics; Pharmacology & Pharmacy; pharmacokinetics; SERUM CONCENTRATIONS; Life Sciences & Biomedicine; Science & Technology; cycloserine; MOXIFLOXACIN; PSYCHOSIS; Microbiology
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

Limited pharmacokinetic/pharmacodynamic (PK/PD) data exist on cycloserine in tuberculosis (TB) patients. We pooled several studies into a large PK data set to estimate the population PK parameters for cycloserine in TB patients. We also performed simulations to provide insight into optimizing the dosing of cycloserine. TB patients were included from Georgia, Bangladesh, and four U.S. sites. Monolix and mlxR package were used for population PK modeling and simulation. We used PK/PD targets for time above MIC of 30% and 64%, representing bactericidal activity and 80% of the maximum kill, to calculate the probability of target attainment (PTA). Optimal PK/PD breakpoints were defined as the highest MIC to achieve 90% of PTA. Data from 247 subjects, including 205 patients with drug-resistant TB, were included. The data were best described by a one-compartment model. In most cases, the PK/PD breakpoints for the simulated regimens were similar for both PK/PD targets. Higher PTA were achieved as the total daily dose was increased. The highest PK/PD breakpoint that resulted from the use of 250 mg dosages was 16 mg/ liter. For MICs of 16 mg/liter, doses of at least 500 mg three times daily or 750 mg twice daily were needed. In conclusion, the current dosing for cycloserine, 250 to 500 mg once or twice daily, is not sufficient for MICs of 16mg/liter. Further studies are needed regarding the efficacy and tolerability of daily doses of 1,000 mg. Dividing the dose minimally affected the PK/PD breakpoints while optimizing exposure, which can potentially reduce adverse drug effects.