Risk of Tacrolimus Toxicity in CYP3A5 Nonexpressors Treated With Intravenous Nicardipine After Kidney Transplantation

Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Transplantation (Impact Factor: 3.83). 04/2012; 93(8):806-12. DOI: 10.1097/TP.0b013e318247a6c7
Source: PubMed


Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5.
We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose-adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases.
Eight cases not expressing CYP3A5 (CYP3A5*3/*3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A5*1/*1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A5*3/*3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A5*1/*1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A5*3/*3 cases vs. all others).
CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity.

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    • "Discovering new SNPs which can determine the onset of ADR or affect treatment efficacy will allow for the use of personalized therapeutic regimens that are free from side effects. For example, immunosuppressant drugs such as Tacrolimus (currently used in the management of solid organ transplant recipients) are also extensively metabolized by CYP3A isoenzymes [22-25]. In this context, our study may also be useful for further analyzing SNPs with significant influence on the metabolism and/or inter-individual pharmacokinetic variability of Tacrolimus in tranplants. "
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