014: Analyzing the Association Between Single Nucleotide Polymorphisms & Combinations of Buprenorphine & Associated Metabolite Concentrations

Statement of Purpose, Innovation or Hypothesis: As the opioid crisis continues to be a problem among pregnant women in the United States, the prevalence of neonatal abstinence syndrome (NAS) consequently continues to cause troublesome effects. To reduce the incidence of NAS, pregnant women receive medicated-assisted treatments, preferably buprenorphine (BUP). However, BUP has risks of fetal toxicity. When metabolized, BUP produces several biologically active metabolites, including norbuprenorphine (NBUP), buprenorphine-3-glucuronide (BUP-Gluc), and norbuprenorphine-3-glucuronide (NBUP-Gluc). Previously, we reported significant associations of several single nucleotide polymorphisms (SNPs) with individual concentrations of BUP or its metabolites. However, there is currently limited data on the association between particular SNPs with BUP in combination with its metabolites or a combination of metabolites. In this subsection study, BUP and its metabolites were tested to determine the association between observed SNPs and various concentration combinations.

Description of Methods & Materials: The prospective observational cohort study investigated the utilization of BUP in pregnant women and its impact on newborns. Neonates were closely monitored for NAS, with appropriate measures taken to ensure their well-being. With maternal consent, fetal umbilical cord blood samples were collected and analyzed for BUP and its metabolites via LC-MS. In this study, an iPLEX ADME PGx, Pro V1.0 panel was used to genotype 15 samples. Relationships between SNPs and concentrations were assessed using the PLINK v1.7 software program. with statistical significance set at p < 0.05. Concentration values are reported as mean ± standard deviation.

Data & Results: Fourteen unique SNPs were identified to be significant (p  < 0.05) across the concentration combinations tested. Of these, six were associated with BUP + BUP-Gluc (22.24 ± 11.29 ng/mL): rs1801265, rs4124874, rs2273697, rs4149117, rs7311358, and rs7294. Four SNPs (rs55785340, rs4244285, rs762551, and rs35742686) were found to be associated with BUP + NBUP (22.08 ± 8.28 ng/mL). Cumulative BUP-Gluc + NBUP-Gluc (41.80 ± 24.32 ng/mL) was associated with rs1801265, rs4124874, rs1143672, rs2273697, rs3740066, rs4149117, rs7311358, and rs3745274. The NBUP + NBUP-Glu combination (41.62 ±19.16 ng/mL) was associated with rs4244285 and rs1058930. The combination of BUP-Gluc + NBUP + NBUP-Gluc (57.59 ± 25.21 ng/mL) was found to be associated with rs1143672. Finally, the combination of BUP + BUP-Gluc + NBUP + NBUP-Gluc (60.94 ± 28.08 ng/mL) was associated with rs1801265, rs4124874, rs1143672, rs2273697, rs3740066, rs4149117, rs7311358, rs3745274.

Interpretation, Conclusion or Significance: Our study revealed relationships between polymorphism and detected drug and metabolite concentration combinations. This highlights the importance of pharmacogenetics in assessing the correlation between combined drug and metabolite concentrations, SNPs, and overall usage of BUP during pregnancy. More research is needed to investigate the clinical influence of certain SNPs which might be linked to NAS.