Kidney Week

Abstract: FR-PO1231

Concordance Between Concentration-to-Dose Ratio and CYP3A5 Genotype and Effect on Pharmacokinetics in Kidney Transplant Recipients Receiving Immediate-Release Tacrolimus

Session Information

• Transplantation: Clinical - Rejection, Biomarkers, and Pharmacology
  October 23, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

• 2002 Transplantation: Clinical

Authors

• Horwedel, Timothy A., Veloxis Pharmaceuticals Inc, Cary, North Carolina, United States

Timothy A. Horwedel, PharmD, RPh

• Masters, Brian, Veloxis Pharmaceuticals Inc, Cary, North Carolina, United States

Brian Masters, PharmD

• Thölking, Gerold, Department of Internal Medicine and Nephrology, Herz-Jesu-Hospital Münster-Hiltrup, Munster-Hiltrup, Germany

Gerold Thölking, MD

Background

In kidney transplant recipients (KTR) on tacrolimus (Tac), the trough concentration-to-dose (C/D) ratio characterizes metabolic phenotypes. A C/D ratio <1.05 ng/mL/mg is often linked to rapid metabolism and poorer outcomes. However, existing thresholds were largely derived from Western European populations with low CYP3A5*1 frequency. This study evaluates Tac pharmacokinetics (PK) and genetics in a diverse cohort to validate the C/D ratio as a risk stratification tool.

Methods

This post-hoc analysis of two phase 3b studies of 76 stable KTR evaluated the impact of CYP3A5 genotype on PK of immediate-release (IR)-Tac. C/D ratios < 1.05 defined KTR as rapid metabolizers, ≥1.05 as slow metabolizers. The C/D-based metabolizer phenotype was compared against CYP3A5*1 genotype, and PK parameters including area under the curve (AUC), maximum (Cmax), and minimum concentration (Cmin). To assess performance of the C/D ratio in identifying presence of the *1 allele, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated.

Results

KTR were a mean age of 49.4 (+11) years, 58% male, 70% black or African-American, with a mean time from transplantation of 4.1 (+3.2) yr. 49 (64%) participants were expressors of the CYP3A5*1 allele, with 15 (20%) homozygous. Based on C/D categorization, 31 were non-RM and 44 were RM. Using the 1.05 threshold for determining presence of *1 allele yielded sensitivity of 86%, specificity of 65%, PPV of 78% and NPV of 77%. The C_min across groups was similar, while AUC and C_max were significantly higher for rapid metabolizers (Table 1).

Conclusion

The C/D ratio of IR-Tac correlates with CYP3A5 genotype, supporting the C/D ratio as a prognostic tool in a broader population. Estimation of C/D ratios in the post-transplant setting may allow for identification of high-risk patients and implementation of mitigation strategies and/or more intensive monitoring for nephrotoxicity-related outcomes. Further clinical trials are needed in this regard.

Pharmacokinetics of IR-tacrolimus in different metabolizers groups

Results presented as mean +/- SD; p values are two-sided from t-test comparing means

Funding

• Commercial Support – Veloxis Pharmaceuticals