Development and Validation of a Genotype Guided Tacrolimus Dosing Equation for African American (AA) Kidney Transplant Recipients

K. Sanghavi,¹ R. Brundage,¹ M. Miller,² D. Schaldt,³ A. Israni,³ W. Guan,⁴ W. Oetting,¹ R. Mannon,⁵ R. Remmel,¹ A. Matas,⁶ P. Jacobson.¹

¹College of Pharmacy, University of MN, Minneapolis, MN
²Dept of Psychology, University of MN, Minneapolis, MN
³Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN
⁴Dept of Biostatistics, University of MN, Minneapolis, MN
⁵Dept of Nephrology, University of AL, Birmingham, AL
⁶Dept of Surgery, University of MN, Minneapolis, MN.

Meeting: 2015 American Transplant Congress

Abstract number: C276

Keywords: Gene polymorphism, Immunosuppression, Monitoring, Pharmacokinetics

Session Information

Session Name: Poster Session C: Translational Biomarkers and Immune Monitoring

Session Type: Poster Session

Date: Monday, May 4, 2015

Session Time: 5:30pm-6:30pm

Presentation Time: 5:30pm-6:30pm

Location: Exhibit Hall E

Tacrolimus (tac) has a strong exposure-response relationship with high inter-individual variability in troughs and dose. Tac dose requirements for AA patients are higher than Caucasians, in part due to high frequency of the CYP3A5*1 allele which enhances tac clearance. However, some AAs have dose requirements similar to Caucasians which may be due to the presence of additional variants. The objective was to determine the effect of other genetic variants on tac troughs and to develop a personalized dosing equation specific for AA, accounting for these variants. Recipients who received tac were studied and divided into a development (n=212 with 3704 troughs) and a validation cohort (n=142 with 2333 troughs). Subjects were genotyped for CYP3A5*3, CYP3A5*6, CYP3A5*7, POR*28 and CYP3A4*22. Population pharmacokinetics was used to develop a tac clearance (Cl/F) model in the test cohort. Forward inclusion/backward elimination identified significant clinical factors (steroid and antiviral use, age) and genotypes. Tacrolimus typical Cl/F decreased by 36.2% in patients carrying the CYP3A5*3/*6 or CYP3A5*6/*7 and by 51.2% if carrying CYP3A5*3/*3 or CYP3A5*3/*7. The CL/F equation is below.

Tacrolimus CL/F (L/h) = 48.9 L/hr x [(1.33, if days less than 9 post-transplant) x [(0.488, if CYP3A5*3/*3 or CYP3A5*3/*7 genotype) or (0.628, if CYP3A5*3/*6 or CYP3A5*6/*7 genotype)] x (0.866, if CYP3A5*1/*3 or CYP3A5*1/*6 or CYP3A5*1/*7 genotype) x (1.24, if receiving a steroid) x (1.09 if not receiving an antiviral) x (1.26 if recipient age between 18-25 yrs)

Once an individuals CL/F is estimated the dose to achieve any given tac trough can be calculated by: total daily dose = CL/F x trough goal x 24 hrs /1000. The model was validated in the validation cohort. This is the first to provide an AA specific tac dosing algorithm to personalize therapy. This may reduce the time required to achieve target tac blood concentrations, reduce the number of dose modifications and the amount of therapeutic drug monitoring.

To cite this abstract in AMA style:

Sanghavi K, Brundage R, Miller M, Schaldt D, Israni A, Guan W, Oetting W, Mannon R, Remmel R, Matas A, Jacobson P. Development and Validation of a Genotype Guided Tacrolimus Dosing Equation for African American (AA) Kidney Transplant Recipients [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/development-and-validation-of-a-genotype-guided-tacrolimus-dosing-equation-for-african-american-aa-kidney-transplant-recipients/. Accessed November 23, 2024.

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