Influence of Absorption, Distribution, Metabolism, and Excretion Genomic Variants on Tacrolimus/Sirolimus Blood Levels and Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation.
Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus-based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non-T-carriers were associated with higher blood levels (P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 (P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1, after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM.
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California; Gehr Family Center for Leukemia Research of the Hematologic Malignancies and Stem Cell Transplantation Institute of the City of Hope, Duarte, CA. Electronic address: samerkm@yahoo.com.
Samer K
SK
Khaled
Division of Biostatistics, City of Hope, Duarte, California.
Joycelynne M
JM
Palmer
Division of Clinical Cancer Genetics, City of Hope, Duarte, California.
Josef
J
Herzog
Division of Biostatistics, City of Hope, Duarte, California.
Tracey
T
Stiller
Division of Biostatistics, City of Hope, Duarte, California.
Ni-Chun
NC
Tsai
Division of Histocompatibility (HLA Laboratory), City of Hope, Duarte, California.
David
D
Senitzer
Division of Biostatistics, City of Hope, Duarte, California.
Xueli
X
Liu
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
Sandra H
SH
Thomas
Department of Pharmacy, City of Hope, Duarte, California.
Sepideh
S
Shayani
Division of Clinical Cancer Genetics, City of Hope, Duarte, California.
Jeffrey
J
Weitzel
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
Stephen J
SJ
Forman
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
Ryotaro
R
Nakamura
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology* / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous / Q000379:methods*; D055815:Young Adult
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus
Drug absorption, distribution, metabolism, and excretion (ADME); Immunosuppressant; Pharmacogenetics