MSACL 2019 EU Abstract

Therapeutic Drug Monitoring of Clofazimine in Indian MDR-TB Patients

Prerna K. Chawla (1), Rohan V. Lokhande (1), Prasad R. Naik (1), Alpa J. Dherai (1), Zarir F. Udwadia (2), Ashok A. Mahashur (2), Lancelot Pinto (2), Rajeev Soman (2), Camilla Rodrigues (1), Jai Mullerpattan (2), Ayesha Sunavala (2) Amita Gupta (3), Jeffrey A Tornheim (3), Neil Martinson (4), Ebrahim Variava (4), Lubbe Wiesner (5), Anton Joubert (5), Tester F. Ashavaid (1)
(1) Dept. of Lab Medicine, P.D. Hinduja Hospital & MRC, Mahim, Mumbai, India (2) Dept. of Pulmonary Medicine, P.D. Hinduja Hospital & MRC, Mahim, Mumbai, India (3) Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA (4) Perinatal HIV Research Unit, Soweto, South Africa (5) University of Cape Town, South Africa

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Prerna Chawla (Presenter) P.D. HINDUJA HOSPITAL & MRC

Presenter Bio: Research Associate & site co-ordinator for NIH studies at the P.D. Hinduja Hospital and Medical Research Centre, a tertiary private healthcare center in central Mumbai, India that extends state-of-art medical care in all branches of medicine and surgery.After completing my Bachelors(2009) and Masters(2011) in Biochemistry under University of Mumbai,I completed my Doctorate in Applied Biology(2017) from University of Mumbai. Being associated with Hinduja Hospital during my Doctorate & under the mentorship of Dr Tester Ashavaid, has given me immersed experience in TDM & Molecular Biology.Currently as a Post-Doctoral Fellow, I am working on TDM of second line anti-TB drugs including the new drugs–Bedaquiline & Delamanid and establishing a prospective MDR TB cohort. We are also a part of successful collaboration with the PHRU,South Africa which is ongoing with co-enrolments in this cohort.

Relevant Financial Disclosures (within past 24 months) Salary Salary from P.D. Hinduja Hospital & MRC Discussing Products? YES, presenter will present educational content related to products/services of one or more ineligible company(ies) listed above. Conflict mitigation IN PROCESS.

INTRODUCTION: Clofazimine (CFZ) is used as a second line drug for multidrug resistant tuberculosis (MDR-TB) treatment. It exerts slow bactericidal effect on mycobacteria by binding to DNA, leading to cell cycle disruption. CFZ is well absorbed orally with food but has a very long half-life. Its pharmacokinetics (PK) is not well understood especially in drug resistant TB patients where treatment monitoring & adherence play a vital role. There is limited literature on CFZ PK with only 3 - 4 labs testing CFZ drug levels globally. Efficient in vitro and in vivo activities against drug resistant strains and low rates of CFZ resistance have promoted its use in MDR-TB therapy.
OBJECTIVES: The present study aimed to quantitate CFZ levels in patients on ongoing MDR therapy.
METHODS: CFZ quantitation was standardized and validated with a tandem mass spectrometry approach using liquid chromatography mass spectrometry (LC-MS). Plasma samples were deproteinized with organic solvents and analysed on LC-MS from a calibration range of 0.0313-4mg/L. Sparse PK plasma levels (pre-dose and 2 hours post dose) were quantitated on 318 samples from 61 treatment-naive patients with MDR TB. These patients have followed up at months 1, 2, 6, and 12 of treatment respectively. The therapeutic range established in literature for CFZ is 0.5-2mg/L.
RESULTS: The method was validated for linearity, accuracy, precision, recovery, and limit of quantitation and stability. Sixty one patients were assessed with a median age of 26 years (interquartile range [IQR] 19-34), 33% and 67% men and women, respectively, and a median weight of 54.3 kg (IQR 44.7-62.9). All patients were on standard doses of 100mg/day CFZ. Though the pre-dose and 2 hour post dose CFZ levels for most patients were very close, the difference was statistically significant. Significantly low median CFZ levels were observed at month 1 (0.336mg/L, IQR 0.22-0.44) and month 2 (0.453 mg/L, IQR 0.35-0.63) when compared with month 6 (0.728 mg/L, IQR 0.62 – 0.92) and month 12 (0.904 mg/L, IQR 0.78-1.0) of treatment.
CONCLUSION: Therapeutic CFZ levels are attained after 6 months in most patients. Increasing the CFZ dose in first 2 months of treatment till therapeutic levels are attained is worth exploring.
Key words: Clofazimine, Second line anti-TB drug, MDR-TB, Therapeutic Drug Monitoring, LC-MS.