Pediatric tuberculous meningitis: model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children

Citation: Savic RM, Ruslami R, Hibma JE, Hesseling A, Ramachandran G, Ganiem AR, Swaminathan S, McIlleron H, Gupta A, Thakur K, van Crevel R, Aarnoutse R, Dooley KE. Pediatric tuberculous meningitis: model-based approach to determining optimal doses of the anti-tuberculosis drugs rifampin and levofloxacin for children. Clin Pharmacol Ther. 2015 Dec;98(6):622-9. doi: 10.1002/cpt.202. Epub 2015 Oct 22. PMID: 26260983. PMCID: PMC4888594.

Access full article:

http://www.ncbi.nlm.nih.gov/pubmed/26260983

Pediatric TB meningitis (TBM) is a highly-morbid, oft-fatal disease. Standard treatment includes isoniazid, rifampin, pyrazinamide, and ethambutol. Current rifampin dosing achieves low cerebrospinal fluid (CSF) concentrations, and CSF penetration of ethambutol is poor. In adult trials, higher-dose rifampin and/or a fluoroquinolone reduced mortality and disability. To estimate optimal dosing of rifampin and levofloxacin for children, we compiled plasma and CSF pharmacokinetic and outcomes data from adult TBM trials plus plasma pharmacokinetic data from children. A population pharmacokinetic/pharmacodynamic model using adult data defined rifampin target exposures (plasma AUC0-24 =92 mg*h/L). Levofloxacin targets and rifampin pediatric drug disposition information were literature-derived. To attain target rifampin exposures, children require daily doses of at least 30 mg/kg orally or 15 mg/kg intravenously. From our pediatric population PK model, oral levofloxacin doses needed to attain exposure targets were 19-33 mg/kg. Our results provide data-driven guidance to maximize pediatric TBM treatment while we await definitive trial results. This article is protected by copyright. All rights reserved.

Clin Pharmacol Ther. 2015 Aug 11. doi: 10.1002/cpt.202. [Epub ahead of print]. PMID: 26260983 [PubMed - as supplied by publisher]

Categories

CRS
Topics

Clinical Trials

A5302:  BioBank for Surrogate Marker Research for TB...

Primary Objective To obtain sputum, serum, urine, and peripheral blood mononuclear cells (PBMCs) for central TB biorepository...

Read More

A5384: A Phase II, Randomized, Open-Label Trial of a...

Study Description A5384 is a trial for people who have or might have tuberculous meningitis (TBM). TBM is an infectious disease...

Read More

P1108: A Phase I/II, Open-Label, Single Arm Study to...

This purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of bedaquiline (BDQ) in...

Read More

The Pharmacokinetics, Safety and Acceptability of New...

PK, safety and acceptability data and practical guidance on the optimal dosing of new more child-friendly formulations of...

Read More

P2005: A Phase I/II Open-Label, Single-Arm Study to Evaluate...

This study is currently on hold. The study is designed to characterize the pharmacokinetics of DLM using a model-based...

Read More