Noninvasive 11 C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis

• Published in: Science translational medicine Vol. 10; no. 470
• Main Authors: Tucker, Elizabeth W, Guglieri-Lopez, Beatriz, Ordonez, Alvaro A, Ritchie, Brittaney, Klunk, Mariah H, Sharma, Richa, Chang, Yong S, Sanchez-Bautista, Julian, Frey, Sarah, Lodge, Martin A, Rowe, Steven P, Holt, Daniel P, Gobburu, Jogarao V S, Peloquin, Charles A, Mathews, William B, Dannals, Robert F, Pardo, Carlos A, Kannan, Sujatha, Ivaturi, Vijay D, Jain, Sanjay K
• Format: Journal Article
• Language: English
• Published: United States 05.12.2018
• Subjects: Animals; Antitubercular Agents - pharmacology; Antitubercular Agents - therapeutic use; Brain - pathology; Carbon Radioisotopes - chemistry; Dose-Response Relationship, Drug; Female; Humans; Male; Positron-Emission Tomography; Probability; Rabbits; Rifampin - pharmacokinetics; Rifampin - pharmacology; Rifampin - therapeutic use; Time Factors; Tissue Distribution - drug effects; Tuberculosis, Meningeal - diagnostic imaging; Tuberculosis, Meningeal - drug therapy
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aau0965

Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experimentally induced TBM and performed serial noninvasive dynamic C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (≥30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues.