Pharmacokinetics of Inhaled Clofazimine in Mice

Tuberculosis (TB) is primarily an infectious disease of lungs caused by Mycobacterium tuberculosis. Despite current therapeutic approaches, it continues to be a serious disease killing more than 1 million people annually. In developed countries, TB treatments conventionally last six-month and involve multiple anti-tubercular agents. Inappropriate treatment implementation, patient non-compliance and extensive treatment regimen has led to increasing prevalence of multidrug resistant (MDR) and extremely drug resistant (XRD) Mycobacterial strains. Therefore, there is an urgent need for alternative TB treatments including the development of new anti-mycobacterial drugs or repurposing of existing antibiotics. Clofazimine (CFZ) is one example of a repurposed antibiotic that is currently approved for the treatment of leprosy. Recently, it gained interest for the treatment of TB as a second line agent in the treatment of MDR and XDR-TB by the World Health Organization (WHO). However, oral CFZ therapy induces serious adverse effects including the discoloration of skin, and conjunctiva, and localized inflammation in GI causing abdominal pain, and splenic infarction. A study published in 2013 established inhaled CFZ as a potential treatment for pulmonary TB. As a result, recent reports describe inhaled CFZ formulation development. The purpose of this study is to evaluate in vivo pharmacokinetics (PK) of inhaled CFZ in healthy male Swiss Webster mice. Mice were divided in 2 major groups that received a single inhaled CFZ dose while the other received multiple inhaled CFZ doses twice weekly for 4 weeks followed by a washout period (no doses) for 4 weeks. Mice in both the groups received either a low or high dose inhaled CFZ. Animals were euthanized at set time points and blood and tissues were collected for quantification of CFZ in biological matrices using a LC-MS method. Pharmacokinetic evaluation of CFZ in plasma and tissues after single and multiple inhaled doses was performed using Non-Compartmental Analysis by Phoenix WinNonlin. Following a single inhaled CFZ dose, substantial drug retention in plasma and tissues occurs for 72 hr with no discernable elimination phase and minimum systemic absorption. After multiple doses, substantial CFZ accumulation occurs in tissues during active dosing and can persist for 4 weeks even after inhaled CFZ doses were stopped. Substantial lung concentrations were found to be of several orders of magnitude higher than plasma concentration indicating low systemic CFZ exposure following inhalation. Inhaled CFZ administration suggests dose independent PK parameters with very long CFZ elimination processes.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2021

Author dc:creator

• Agrawal, Prachi

Advisor dc:contributor.advisor

• Tolman, Justin A.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10504/133757

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/133757