EP-011 - METABOLIC PROFILE INVESTIGATION REVEALS WIDE VARIABILITY IN THE EXPOSURE OF ISONIAZID AND ITS HEPATOTOXIC METABOLITES IN TUBERCULOSIS PATIENTS.

N. Anh¹, P. Tung ¹, T. Jang², J. Min³, J. Kim⁴, J. Oh⁵, H. Lee⁶, H. Lee⁷, H. Kim⁸, H. Park⁹, H. Lee¹⁰, I. Park¹¹, J. Mok¹², J. Lee¹³, S. Ahn¹, N. Long¹, Y. Cho¹, J. Shin¹, D. Kim¹; ¹Inje University, Busan, Republic of Korea, ²Kosin University, Busan, Republic of Korea, ³The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Republic of Korea, ⁴The Catholic University of Korea, Incheon St. Mary's Hospital, Incheon, Republic of Korea, ⁵Korea University Guro Hospital, Seoul, Republic of Korea, ⁶Inje University Busan Paik Hospital, Busan, Republic of Korea, ⁷The Catholic University of Korea, Eunpyeong St. Mary's Hospital, Seoul, Republic of Korea, ⁸Inje University Haeundae Paik Hospital, Busan, Republic of Korea, ⁹Inje University Ilsan Paik Hospital, Ilsan, Republic of Korea, ¹⁰Inje University Sanggye Paik Hospital, Seoul, Republic of Korea, ¹¹Inje University Seoul Paik Hospital, Seoul, Republic of Korea, ¹²Pusan National University Hospital, Busan, Republic of Korea, ¹³Kyungpook National University Hospital, Daegu, Republic of Korea.

Background: Isoniazid (INH) is a first-line agent for the treatment of tuberculosis (TB), a global health crisis. INH and its metabolites exposure variability could influence the effectiveness and toxicity of INH-based therapy. To assess the interindividual differences in INH metabolism and distribution we investigated the impact of clinical and pharmacogenetic factors on the metabolic profiles of the drug.

Methods: A targeted profiling of INH and its four major metabolites (i.e., acetylisoniazid, isonicotinic acid, hydrazine, and acetylhydrazine) in plasma of 965 TB patient was performed using liquid chromatography-tandem mass spectrometry. N-acetyltransferase 2 (NAT2) genotypes were also determined for patients' acetylator phenotypes. After removing non-compliance subjects, 876 TB patients' INH metabolic profiles, including 345 rapid, 412 intermediate and 119 slow acetylator, were selected for subsequent analyses. The distribution of INH and its metabolites was examined during 24 h time-course to characterize their exposure variabilities in different acetylators and clinical factors.

Results: The median concentration of INH in its time-course was 2.5-fold and 1.8-fold higher in slow acetylator compared to rapid and intermediate acetylator, respectively. Median concentrations of hydrazine, the hepatotoxic metabolite, were over 1.7-fold higher in slow acetylator compared to other NAT2 phenotypes. The metabolic ratio distribution of INH was significantly associated with NAT2 phenotypes.

Conclusion: INH metabolic profiles are markedly associated with acetylator phenotypes of TB patients. Our findings provide a proof of concept toward implementing an acetylator phenotype-based dosing for a safe and effective INH-based therapy.