Impact of genetic polymorphisms of drug-metabolizing enzymes SLCO1B1 and AADAC on rifampicin pharmacokinetics and adverse outcomes: A systematic review and meta-analysis
Creators: name: Liu, Yutong
Publisher: name: Stanford Digital Repository
Year: 2024
Subjects: subject: Tuberculosis
subject: Pharmacogenomics
subject: FOS: Medical biotechnology
subject: Pharmacodynamics

description: Background
Rifampicin (RIF) is a cornerstone in tuberculosis (TB) treatment, but its efficacy and safety may be influenced by genetic variations in drug-metabolizing enzymes (DMEs). Existing pharmacogenomic studies have reported mixed effects of single nucleotide polymorphisms (SNPs) for key DMEs SLCO1B1 and AADAC on RIF pharmacokinetics and adverse events. Understanding these variations is crucial for optimizing TB treatment and minimizing the risk of adverse outcomes and poor TB treatment outcomes.
Objective
To summarize and estimate the impact of genetic polymorphisms in SLCO1B1 and AADAC on pharmacokinetics and adverse events for rifampicin through a systematic review and meta-analysis.
Methods
We conducted a comprehensive search in PubMed, EMBASE, and Web of Science for studies published up to April 2024. Keywords included terms relating to SLCO1B1, AADAC, pharmacogenetics, pharmacokinetics, and adverse events. Eligible studies included observational and interventional designs that examined the association between SLCO1B1 or AADAC polymorphisms and rifampicin pharmacokinetics or drug-induced liver injury (DILI) outcomes. For each SNP, outcomes were compiled into wildtype and mutant carrying groups, with the mutant carrying group capturing outcomes for both heterozygous and homozygous variants and considered the exposed group. Meta-analyses were performed to calculate mean differences for pharmacokinetic outcomes and pooled odds ratios (ORs) for adverse events using a random effects model. Heterogeneity across studies was assessed using the I2 statistic.
Results
Three hundred and fourteen articles were identified, of which 29 studies met the inclusion criteria for this systematic review, with 9 studies included in the final meta-analysis. Maximum serum concentration (Cmax) and DILI were two main outcomes with sufficient data for pooled analysis. SLCO1B1 SNPs rs4149056 and rs2306283 were identified as SNPs with sufficient data for those outcomes with none of the SNPs for AADAC having sufficient data for pooled analysis. For pharmacokinetics, SLCO1B1 SNP rs4149056 showed no significant effect on Cmax, with a mean difference of 0.29 μg/ml (95% CI: -1.99 to 1.41). In terms of liver injury, the pooled odds of all liver injury events for individuals in the mutant carrying group for SLCO1B1 SNP rs2306283 was 0.74 times (95% CI: 0.48–1.14) those for the wildtype carrying group. For SLCO1B1 SNP rs4149056, the pooled odds of all liver injury events for individuals in the mutant carrying group was 1.42 times (95% CI: 0.85–2.35) those for the wildtype carrying group, indicating a potential increased risk for the mutant carrying group.
Conclusions and Relevance
Our findings suggest that SLCO1B1 SNPs rs2306283 and rs4149056 do not have statistically significant impacts on Cmax or liver injury. However, the potential protective effect of rs2306283 against liver injury and the increased liver injury risk associated with rs4149056, suggest that these genetic variations may still have clinical relevance despite minimal impact on Cmax. There is a need for standardized methodologies and comprehensive data reporting in pharmacogenetic research to fully elucidate the complex roles of SLCO1B1, AADAC and other pharmacogenetic factors in TB treatment outcomes.