Date: Sunday, June 6, 2021
Session Time: 6:00pm-7:00pm
Presentation Time: 6:20pm-6:25pm
*Purpose: Mycophenolic acid (MPA), exhibits interpatient pharmacokinetic (PK) variability attributed to enterohepatic circulation of the glucuronide metabolite (MPAG) to MPA. This is mediated by multidrug resistance-associated protein 2(MRP2), which is encoded by ABCC2. MPAG conversion contributes to MPA PK variability and may be impacted by calcineurin inhibitors or transporter polymorphisms. This study investigated ABCC2 haplotypic associations to MPA pharmacokinetics in stable renal transplant recipients receiving calcineurin inhibiters.
*Methods: Pharmacogenomic analysis of prospective, cross-sectional studies evaluated 147 stable recipients receiving tacrolimus(TAC) and MPA or cyclosporine (CYA) and MPA. MPA pharmacokinetics included trough 12hr, Area Under the Concentration-Time curve 0-12 hours (AUC 0-12hr),and clearance (CL). The MPA therapeutic target exposure (AUC 0-12hr) was 30 to 60 mg•hr/L. The ABCC2 genotypes: ABCC2 1249 C>T(rs2273697); ABCC2 -24C.T (rs717620) and ABCC2 3972 C>T (rs3740066) were determined. Haplotype phenotypic associations were computed using THESIAS(v. 3.1) based upon the Combined Treatment groups (TAC-MPA plus CYA-MPA) with a sub-analysis based upon individual calcineurin inhibitor regimens.
*Results: For the Combined Treatment analysis, 51% of all participants exhibited the wild-type (WT) haplotype, CGC, and had slower MPA CL with greater AUC 0-12hr that was in the target range compared to the 18% of recipients with the variant haplotype, CGT who achieved sub-therapeutic exposure. Similar findings are reported for the Tacrolimus-MPA regimen. No differences were found between the WT and variant haplotype with the Cyclosporine-MPA regimen. See Table below which summarizes significant results of Combined and Tacrolimus-MPA Treatment groups.
*Conclusions: The variant ABCC2 haplotype, CGT, contributes to sub-therapeutic MPA exposures and influences interpatient variability in pharmacokinetic phenotypes when compared with the WT, CGC in the Combined Treatment groups and Tacrolimus-MPA regimens.
|Combined Treatment N=147 (% Participants)||TAC-MPA N=67 (% Participants)|
|MPA PK Mean (±95% Confidence Interval)||WT CGC (51%)||Variant CGT (18%)||P Value||WT CGC (52%)||Variant CGT (22%)||P Value|
|Trough C12hr (mg/L)||1.63 (1.39- 1.87)||1.01 (0.42- 1.61)||0.078||2.25 (1.87- 2.63)||1.33 (0.411- 2.25)||0.081|
|AUC 0-12hr(mg•hr/L)||31.06 (27.83- 34.30)||18.03 (8.40 -27.66)||0.018||39.96 (34.59- 45.32)||20.06 (4.08 -36.0)||0.031|
|Clearance (L/hr)||7.11(5.74 – 8.49)||11.04(8.80 -13.27)||0.013||4.58 (3.53 – 5.63)||7.22 (5.7- 8.73)||0.014|
To cite this abstract in AMA style:Tornatore K, Brazeau D, Meaney C, Consiglio J, Gundroo A, Chang S, Wilding G, Cooper L. ABCC2 Haplotypes Associations to Mycophenolic Acid Pharmacokinetics in Stable Renal Transplant Recipients [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/abcc2-haplotypes-associations-to-mycophenolic-acid-pharmacokinetics-in-stable-renal-transplant-recipients/. Accessed October 15, 2021.
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