Pharmacogenetics in immunosuppressants: impact on dose requirement of calcineurin inhibitors in renal and liver pediatric transplant recipients

Abstract

Calcineurin inhibitors (CNI) are the mainstay immunosuppressive therapy in pediatric solid organ transplantation. These drugs have narrow therapeutic window, and continuous therapeutic drug monitoring is required to keep blood levels within the therapeutic range. Personalization of immunosuppressive therapy according to the genetic profile may provide a way to optimize drug dosing from the first day of transplantation. In this review, we will highlight the recent pharmacogenetic studies of CNIs in pediatric renal and liver transplantation. CNIs are metabolized by CYP3A4 and CYP3A5. In the intestine, the absorption of these drugs is limited by the P-glycoprotein efflux transporter. Most of the pediatric studies showed an association between CYP3A5 genetic variation and CNI dosing. Carriers of the wild-type allele (CYP3A5*1) required higher doses of CNIs as compared with individuals homozygous to the variant CYP3A5*3 allele. CYP3A4 and ABCB1 (encoding P-glycoprotein) genetic variations did not show an association with CNI dosing. The pharmacogenetics of CNIs has been widely investigated in adults, little is known about this field in the pediatric groups. Prospective studies are needed to elucidate the effect of genetic variations on CNI drug dosing and to investigate their impact on short and long-term clinical outcome.