Journal article
Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
Antimicrobial agents and chemotherapy, Vol.63(5), e00055-19
05/01/2019
DOI: 10.1128/AAC.00055-19
PMCID: PMC6496076
PMID: 30858211
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 >16 mg/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.
Details
- Title: Subtitle
- Cycloserine Population Pharmacokinetics and Pharmacodynamics in Patients with Tuberculosis
- Creators
- Wael A. Alghamdi - King Khalid UniversityAbdullah Alsultan - King Saud UniversityMohammad H. Al-Shaer - University of FloridaGuohua An - University of IowaShahriar Ahmed - International Centre for Diarrhoeal Disease ResearchYosra Alkabab - University of VirginiaSayera Banu - International Centre for Diarrhoeal Disease ResearchKetevan Barbakadze - National Center for Tuberculosis and Lung DiseaseEric Houpt - University of VirginiaMaia Kipiani - National Center for Tuberculosis and Lung DiseaseLali Mikiashvili - National Center for Tuberculosis and Lung DiseaseStephan Schmidt - University of FloridaScott K. Heysell - University of VirginiaRussell R. Kempker - Emory UniversityJ. Peter Cegielski - The University of Texas Health Science Center at TylerCharles A. Peloquin - University of Florida
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.63(5), e00055-19
- DOI
- 10.1128/AAC.00055-19
- PMID
- 30858211
- PMCID
- PMC6496076
- NLM abbreviation
- Antimicrob Agents Chemother
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Publisher
- Amer Soc Microbiology
- Number of pages
- 11
- Grant note
- K23AI103044 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) OPP1031105 / Bill and Melinda Gates Foundation; Bill & Melinda Gates Foundation D43 TW007124 / National Institutes of Health Fogarty International Center; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC) K23 AI103044; R21 AI122001 / National Institute of Allergy and Infectious Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) U01 AI115594; T32 AI007046-41 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA D43TW007124 / FOGARTY INTERNATIONAL CENTER; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Fogarty International Center (FIC) G-2200 / International Science and Technology Center
- Language
- English
- Date published
- 05/01/2019
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984365885402771
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