Pharmacokinetics of bedaquiline in cerebrospinal fluid (CSF) in patients with pulmonary tuberculosis (TB)

Author:

Upton Caryn M1ORCID,Steele Chanel I2,Maartens Gary2ORCID,Diacon Andreas H1,Wiesner Lubbe2ORCID,Dooley Kelly E3

Affiliation:

1. TASK , Cape Town , South Africa

2. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Cape Town , South Africa

3. Johns Hopkins University School of Medicine , Baltimore, MD , USA

Abstract

Abstract Background With current treatment options most patients with CNS TB develop severe disability or die. Drug-resistant tuberculous meningitis is nearly uniformly fatal. Novel treatment strategies are needed. Bedaquiline, a potent anti-TB drug, has been reported to be absent from CSF in a single report. Objectives To explore the pharmacokinetics of bedaquiline and its M2 metabolite in the CSF of patients with pulmonary TB. Patients and methods Individuals with rifampicin-resistant pulmonary TB established on a 24 week course of treatment with bedaquiline underwent a lumbar puncture along with multiple blood sample collections over 24 h for CSF and plasma pharmacokinetic assessment, respectively. To capture the expected low bedaquiline and M2 concentrations (due to high protein binding in plasma) we optimized CSF collection and storage methods in vitro before concentrations were quantified via liquid chromatography with tandem MS. Results Seven male participants were enrolled, two with HIV coinfection. Using LoBind® tubes lined with a 5% BSA solution, bedaquiline and M2 could be accurately measured in CSF. Bedaquiline and M2 were present in all patients at all timepoints at concentrations similar to the estimated unbound fractions in plasma. Conclusions Bedaquiline and M2 penetrate freely into the CSF of pulmonary TB patients with a presumably intact blood–brain barrier. Clinical studies are urgently needed to determine whether bedaquiline can contribute meaningfully to the treatment of CNS TB.

Funder

National Institute of Allergy and Infectious Diseases

National Institutes of Health

TASK, PanACEA consortium

Radboud University Medical Center

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology,Microbiology (medical)

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