The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation.
BACKGROUND
tacrolimus and everolimus are immunosuppressive drugs metabolized by enzymes of the CYP3A subfamily. A common variant of the CYP3A5 gene, CYP3A5*3, results in strongly decreased CYP3A5 activity and has been shown to influence Tacrolimus blood concentrations, but its role for the pharmacogenetics of Everolimus remains unclear. Aim of the study was to examine the role of CYP3A5*3 variant in tacrolimus and everolimus dose and drug levels after heart transplantation.


METHODS
The present study comprised 15 patients with Tacrolimus and 30 patients with Everolimus-based maintenance therapy after heart transplantation. CYP3A5 genotypes were determined and correlated with clinical data.


RESULTS
In the Tacrolimus group, 13 subjects were CYP3A5 non-expressors (*3/*3 genotype) and two were heterozygous expressors (*1/*3 genotype). Average Tacrolimus dose was significantly higher in subjects expressing CYP3A5 compared to non-expressors. Tacrolimus levels were not significantly different at any point of time. In the Everolimus group, 27 subjects were CYP3A5 non-expressors (*3/*3 genotype) and three were heterozygous expressors (*1/*3). Neither Everolimus dose nor levels were significantly different between CYP3A5 expressors and non-expressors at any point of time.


CONCLUSIONS
We conclude that in adult patients after heart transplantation, CYP3A5 genotypes have a strong influence on Tacrolimus, but not Everolimus dose requirement.
Kniepeiss
Daniela
D
Department of Surgery, Division of Transplantation, Medical University Graz, Graz, Austria. daniela.kniepeiss@meduni-graz.at
Renner
Wilfried
W
Trummer
Olivia
O
Wagner
Doris
D
Wasler
Andrä
A
Khoschsorur
Gholam A
GA
Truschnig-Wilders
Martie
M
Tscheliessnigg
Karl-Heinz
KH
D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000175:diagnosis / Q000235:genetics; D006331:Heart Diseases / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D000068338:Everolimus; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus; D016559:Tacrolimus