Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism – a prospective, randomized, controlled study

Abstract

We investigated how cytochrome P450 (CYP) 3A5 polymorphism affects pharmacokinetics of tacrolimus and its interaction with diltiazem in Chinese kidney transplant recipients. Sixty-two CYP3A5 expressers and 58 non-expressers were, respectively, randomized to receive diltiazem supplement or not. Their pharmacokinetic profiles were acquired on 14th day, sixth month, and 18th month post-transplant and compared among groups. A dosing equation was fit based on above data with CYP3A5 genotype and diltiazem co-administration as variables. Then, necessary initial doses with or without diltiazem were calculated and used in 11 CYP3A5 expressers, respectively, when another 11 expressers received routine doses as control. Trough concentration was measured on the third-day post-transplant and patients failed to reach target range were presented in percentage. These two parameters were compared among three groups. Patients were followed up until June 2010, kidney function, biopsy-proved acute rejection, and other adverse events were monitored. Results showed that CYP3A5 expressers needed more tacrolimus to reach therapeutic concentration window and were more susceptible to diltiazem-induced concentration increase than CYP3A5 non-expressers. CYP3A5 polymorphism-guided dosing equation helped to determine appropriate initial doses of tacrolimus in individuals. In conclusion, CYP3A5 polymorphism profoundly influences pharmacokinetics of tacrolimus and helps to individualize tacrolimus dose.

Long-term outcome of ketoconazole and tacrolimus co-administration in kidney transplant patients

“…Ideally, tacrolimus dosing should be based on a 12 h area under the curve (AUC) that indicates the extent of systemic exposure. In clinical practice, oral doing is usually guided by monitoring 12 h trough levels, because of the convenience for blood sampling and the assumed correlation between trough level and AUC [2,3,12,13] . However, this correlation varies considerably and the best sampling time for a spot tacrolimus level to predict its total body exposure remains controversial [2,3,[12][13][14] .…”

“…In clinical practice, oral doing is usually guided by monitoring 12 h trough levels, because of the convenience for blood sampling and the assumed correlation between trough level and AUC [2,3,12,13] . However, this correlation varies considerably and the best sampling time for a spot tacrolimus level to predict its total body exposure remains controversial [2,3,[12][13][14] . The advance in pharmacogenetics has led the discovery of several gene polymorphisms in P450 family, which explains the inter-individual variability of tacrolimus metabolism [13,15,16] .…”

“…However, this correlation varies considerably and the best sampling time for a spot tacrolimus level to predict its total body exposure remains controversial [2,3,[12][13][14] . The advance in pharmacogenetics has led the discovery of several gene polymorphisms in P450 family, which explains the inter-individual variability of tacrolimus metabolism [13,15,16] . Transplant patients Table 4 Multivariable analysis of risk factors for acute rejection expressing P450-3A5 (expressers) were shown to need higher doses of tacrolimus than non-expressers to reach similar trough levels [13,16] .…”

“…The advance in pharmacogenetics has led the discovery of several gene polymorphisms in P450 family, which explains the inter-individual variability of tacrolimus metabolism [13,15,16] . Transplant patients Table 4 Multivariable analysis of risk factors for acute rejection expressing P450-3A5 (expressers) were shown to need higher doses of tacrolimus than non-expressers to reach similar trough levels [13,16] . Our study suggests that co-administration of ketoconazole with tacrolimus increase the risk of acute rejection.…”

The POR rs1057868–rs2868177 GC-GT diplotype is associated with high tacrolimus concentrations in early post-renal transplant recipients

“…However, the narrow therapeutic window (trough concentration should be controlled in the range of 5 to 8 ng/mL in the first 3 months post-transplant in our routine [2] ) and large inter-individual pharmacokinetic variability are the major therapeutic challenges. Over-immunosuppression causes toxicity and under-immunosuppression leads to rejection, characterizing the highest risks during the initial period, especially within the 7 d post-transplantation [3] .…”