Assessment of Rifampicin Exposure in Latvian Pulmonary Tuberculosis Patients in the Context with AADAC Genetic Polymorphisms

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Description

The anti-tuberculosis (anti-TB) treatment success largely depends on M. tuberculosis drug susceptibility and adequate drug exposure. Rifampicin (RIF), one of the most important drugs in TB treatment, is a substrate of human liver arylacetamide deacetylase (AADAC). Recent studies suggest that polymorphisms in the AADAC gene are associated with RIF pharmacokinetic variability. This study aimed to evaluate RIF exposure in pulmonary TB (PTB) patients considering the AADAC haplotype.. The study population comprised PTB patients (n=58) admitted to the Riga East University Hospital, Centre of Tuberculosis and Lung Diseases. The AADAC haplotype was determined using a targeted NGS-based methodology designed for the analysis of TB-associated pharmacogenes. Sequencing data were processed on Galaxy open-source platform; detected variants were annotated using an online-based wANNOVAR tool. The RIF concentration was measured using LC-MS/MS method in the plasma samples collected pre-dose, 2 h and 6 h post-dose. The statistical data analysis was performed using jamovi software (The jamovi project, v2.3); Quade's rANCOVA was conducted to compare RIF exposure between detected haplotypes considering body weight and dose.. The NGS sequencing results showed that patients were predominately either AADAC*1/*2 or AADAC*2/*2 haplotype carriers (25.9% and 70.7%, respectively). The rare AADAC*1/*1 (wild-type) and AADAC*2/*3 haplotypes were detected in one patient each (1.7%). Overall, the prevalence of lower than recommended RIF plasma concentration (< 8 μg/mL) 2 h post-dose was 93.0%. Further analysis did not reveal any statistically significant differences in adjusted RIF AUC0-6h between the detected AADAC haplotypes (p > 0.05).. The observed RIF underexposure in PTB patients is in line with previously reported findings. However, our results did not indicate the potential impact of the AADAC haplotype on RIF exposure. Further studies are required to identify and assess other factors contributing to RIF underexposure. Acknowledgements. This study was supported by the Latvian Council of Science, project No. lzp-2020/1-0050.
Period29 Mar 2023
Event titleRSU International Research Conference 2023: Knowledge for Use in Practice
Event typeConference
OrganiserRīga Stradiņš University
LocationRiga, LatviaShow on map
Degree of RecognitionInternational

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