Personalizing initial calcineurin inhibitor dosing by adjusting to donor CYP3A-status in liver transplant patients.
OBJECTIVE
Inter-individual variability in dose requirements of calcineurin inhibitors (CNI) has been linked to genetic polymorphisms of CYP3A enzymes. CYP3A5*3, CYP3A4*1B and CYP3A4*22 alleles of liver grafts may explain about one third of the inter-individual differences in pharmacokinetics of ciclosporin and tacrolimus in recipients. However, non-genetic factors, influencing CYP3A expression, can contribute to the variability of CYP3A function due to phenoconversion. The present study evaluated the association between CYP3A4 expression combined with CYP3A5 genotype of donor livers and recipients' CNI therapy after transplantation.


METHODS
The contribution of donors' CYP3A5 genotype and CYP3A4 expression to the blood concentrations and dose requirements of CNIs was evaluated in 131 liver transplant recipients.


RESULTS
The recipients with grafts from normal CYP3A4 expresser donors carrying CYP3A5*3/*3 required CNI maintenance doses more or less similar to the bodyweight-controlled starting doses (9.1 mg kg(-1) of ciclosporin and 0.1 mg kg(-1) of tacrolimus). The patients transplanted with grafts from low CYP3A4 expressers required substantial reduction (by about 50%, 4.2 mg kg(-1) of ciclosporin, 0.047 mg kg(-1) of tacrolimus, P < 0.001), while the recipients with grafts from high expressers or with grafts carrying at least one copy of the functional CYP3A5*1 allele required an increase (by about 50% [12.8-13.8 mg kg(-1)] for ciclosporin and 100% [0.21 mg kg(-1) ] for tacrolimus, P < 0.001) of the initial CNI dose for achieving target blood concentrations.


CONCLUSIONS
Donor livers' CYP3A-status, taking both CYP3A5 allelic variations and CYP3A4 expression into account, can better identify the risk of CNI over- or underexposure, and may contribute to the avoidance of misdosing-induced graft injury in the early post-operative period.
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117, Budapest.
Katalin
K
Monostory
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117, Budapest.
Katalin
K
Tóth
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117, Budapest.
Ádám
Á
Kiss
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117, Budapest.
Edit
E
Háfra
Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok 2, H-1117, Budapest.
Nóra
N
Csikány
Nucleotest Bio Ltd., Tündérliget 3/2, H-1038, Budapest.
József
J
Paulik
Department of Transplantation and Surgery, Semmelweis University, Baross 23, H-1082, Budapest, Hungary.
Enikő
E
Sárváry
Department of Transplantation and Surgery, Semmelweis University, Baross 23, H-1082, Budapest, Hungary.
László
L
Kóbori
D000328:Adult; D000483:Alleles; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008099:Liver / Q000201:enzymology*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D014019:Tissue Donors
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A
CYP3A status; CYP3A4 expression; CYP3A5 genotyping; ciclosporin; liver transplant recipients; tacrolimus