Tacrolimus is metabolized by cytochrome P450 (CYP) 3A5. The objective of this study was to investigate the influence of the genetic polymorphism of CYP3A5 on the pharmacokinetics of a new ...modified-release, once-daily formulation of tacrolimus (Advagraf®) after a switch from the immediate-release formulation (Prograf®).
This was a prospective, single-centre, open-label study in stable kidney transplant recipients. Seventeen 'expressor' patients (CYP3A5*1/*3 or *1/*1) were matched to 15 'non-expressor' patients (CYP3A5*3/*3). Exposure variables (concentrations and area under the blood concentration-time curve from 0 to 24 hours AUC(24)) were obtained before and 15 days after the switch. Delay since grafting was similar for both groups of patients (expressors: 49 ± 24 months; non-expressors: 45 ± 22 months).
During administration of tacrolimus as Prograf® or Advagraf®, the mean tacrolimus daily dose was significantly higher and the dose-adjusted AUC(24) was significantly lower in the expressor group. Following the switch to Advagraf®, there was a significant decrease in the dose-adjusted AUC(24) for both non-expressor (5910 ± 3019 vs 5334 ± 2668 ng·h/mL per mg/kg/day; p = 0.041) and expressor patients (3701 ± 1409 vs 3273 ± 1372 ng·h/mL per mg/kg/day; p = 0.03). In the non-expressor group, mean blood trough concentration (C(0)) was comparable for both formulations while it decreased significantly in the expressor group after the switch (8.2 ± 2.2 vs 6.3 ± 2.5 ng/mL; p = 0.02). However, a good correlation between AUC(24) and C(0) was observed for both Advagraf® and Prograf® regardless of CYP3A5 genotype.
Tacrolimus exposure significantly decreases after a switch from Prograf® to Advagraf®, on a milligram-for-milligram basis, in CYP3A5 expressor recipients. Consequently, these patients should be carefully monitored.
Strong geographic variations in the incidence of end-stage renal disease (ESRD) are observed in developed countries. The reasons for these variations are unknown. They may reflect regional ...inequalities in the population's sociodemographic characteristics, related diseases, or medical practice patterns. In France, at the district level, the highest incidence rates have been found in the Nord-Pas-de-Calais region. This area, with a high population density and homogeneous healthcare provision, represents a geographic situation which is quite suitable for the study, over small areas, of spatial disparities in the incidence of ESRD, together with their correlation with a deprivation index and other risk factors.
The Renal Epidemiology and Information Network is a national registry, which lists all ESRD patients in France. All cases included in the Nord-Pas-de-Calais registry between 2005 and 2011 were extracted. Adjusted and smoothed standardized incidence ratio (SIR) was calculated for each of the 170 cantons, thanks to a hierarchical Bayesian model. The correlation between ESRD incidence and deprivation was assessed using the quintiles of Townsend index. Relative risk (RR) and credible intervals (CI) were estimated for each quintile.
Significant spatial disparities in ESRD incidence were found within the Nord-Pas-de-Calais region. The sex- and age-adjusted, smoothed SIRs varied from 0.66 to 1.64. Although no correlation is found with diabetic or vascular nephropathy, the smoothed SIRs are correlated with the Townsend index (RR: 1.18, 95% CI 1.00-1.34 for Q2; 1.28, 95% CI 1.11-1.47 for Q3; 1.30, 95% CI 1.14-1.51 for Q4; 1.44, 95% CI 1.32-1.74 for Q5).
For the first time at this aggregation level in France, this study reveals significant geographic differences in ESRD incidence. Unlike the time of renal replacement care, deprivation is certainly a determinant in this phenomenon. This association is probably independent of the patients' financial ability to gain access to healthcare.
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