Jaime Sánchez-Plumed

The pharmacokinetics of mycophenolate mofetil in renal transplant recipients receiving standard-dose or low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the Symphony pharmacokinetic substudy

BACKGROUND Exposure to mycophenolic acid (MPA), the primary active metabolite of mycophenolate mofetil (MMF), is correlated with therapeutic efficacy of MMF but varies depending on the concomitantly administered immunosuppressive drugs. METHODS A 3-month pharmacokinetic substudy of the prospective, randomized, multicentre, open-label Symphony study was performed. Eighty-three adult renal transplant patients received standard-dose cyclosporine, MMF 2 g/day and corticosteroids, or daclizumab induction, MMF 2 g/day and corticosteroids plus low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The area under the concentration-time curve (AUC(0-12)) of MPA and its metabolites between treatment groups was compared. Pharmacokinetic sampling was performed before MMF administration and at 20, 40, 75 min; 2, 3, 6, 8, 10 and 12 h post-dose on Day 7 and Months 1 and 3. RESULTS Compared with standard-dose cyclosporine, patients receiving low-dose tacrolimus or low-dose sirolimus had significantly higher AUC(0-12) values for MPA at Day 7 and Month 1 and for free MPA at Day 7, and significantly lower AUC(0-12) values for 7-O-MPA-glucuronide (MPAG) at Month 1 and for acyl-glucuronide at Months 1 and 3 (P < 0.05). AUC(0-12) of MPA and free MPA was significantly greater with low-dose tacrolimus and low-dose sirolimus than with low-dose cyclosporine in the first month (P < 0.05). The ratio of MPA to MPAG exposure was significantly higher in the three low-dose groups than in the standard-dose cyclosporine group (P < 0.05). CONCLUSIONS Standard- and low-dose cyclosporine reduces the exposure of MPA and free MPA compared to low-dose tacrolimus or low-dose sirolimus in patients given the same dose of MMF.

Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients–results of the Pharmacogenomic Substudy within the Symphony Study

BACKGROUND The aim of this study was to determine the relationship between single-nucleotide polymorphisms (SNPs) in MRP2 genes and mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients of the Symphony Pharmacogenomic substudy. METHODS Sixty-six renal transplant recipients of eight Spanish centres were randomized into four branches of immunosuppressive regimen: low dose of cyclosporine, standard dose of cyclosporine, tacrolimus and sirolimus, all in addition to mycophenolate mofetil and steroids. Fifty-five patients were genotyped for SNPs in MRP2, C24T and C3972T. Pharmacokinetic sampling was done before MPA administration and up to 12 h post-dose at Day 7, 1 month and 3 months post-transplant. Relationships of area under the curve (AUC) of MPA and MPAG plasma sampling with the presence of MRP2 SNPs and with the immunosuppressive regimens were studied. RESULTS At steady-state conditions, MPA-reduced exposure was observed in C24T variant allele in MRP2 (CC: 68.73 ± 6.78; *T: 48.12 ± 4.90, P = 0.023); no significant differences linked to C3972T SNP were observed. Taking into account groups of treatment, lower MPA AUC in variant allele of C24T was only found under macrolides treatment with statistically significant differences at Month 3 (Tac and SRL, CC: 86.52 ± 10.98 versus *T: 41.99 ± 4.82, P = 0.001; CsA, CC: 52.31 ± 5.30 versus *T: 54.24 ± 8.30, P = 0.772); for C3972T, the same tendency was found but differences at steady state did not reach statistical significance. CONCLUSIONS Renal transplant recipients T carriers of C24T MRP2 with macrolides treatment were associated with reduced MPA AUC in steady-state conditions. Patients treated with cyclosporine lost the effect of this polymorphism.

Fluvastatin in the prevention of renal transplant vasculopathy: results of a prospective, randomized, double-blind, placebo-controlled trial.

Background. Statins prevent the progression of transplant vasculopathy in heart transplants, but its beneficial effect on the transplanted kidney is controversial. Methods. The aim is to evaluate the utility of fluvastatin 80 mg/day to reduce the progression of 6-month renal transplant vasculopathy in a multicenter, prospective, randomized, placebo-controlled trial stratified according to donor age. All patients received cyclosporine, mycophenolate mofetil, and prednisone. The progression of transplant vasculopathy was evaluated in paired donor and 6-month protocol biopsies. The primary efficacy variable was the progression of mean arterial intimal volume fraction (&dgr;Vvintima/artery) evaluated with histomorphometry. The minimum sample size to detect a 50% reduction in the progression of &dgr;Vvintima/artery was 62 patients per group. The secondary efficacy variable included the incidence of transplant vasculopathy evaluated according to Banff criteria. Results. A total of 89 patients were included, 74 completed the 6-month study and 57 have paired biopsies with sufficient tissue for histological evaluation. The &dgr;Vvintima/artery was not different between treatment and placebo groups (6.9±8.2% vs. 6.9±7.4%, P=ns), whereas the incidence of transplant vasculopathy was lower in the fluvastatin group (7% vs. 33%; P=0.02). Because there was a discrepancy between the primary and secondary efficacy variables, post hoc analysis was performed to evaluate the reproducibility of both variables in a subset of 50 biopsies. The reproducibility of transplant vasculopathy was higher than the reproducibility of Vvintima/artery (&kgr; 0.86 vs. 0.33). Conclusions. In summary, there were no differences in &dgr;Vvintima/artery between groups, but fluvastatin treatment was associated with a reduced incidence of transplant vasculopathy.

Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients

Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventy-five renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23–39 days), compared with 12 days (95% CI, 10–15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (Cmin/[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to CYP3A5*1/*3 or CYP3A5*1/*1 genotype. Recipients with CYP2C19*2/*2 genotype also showed allograft delayed function (acute tubular necrosis in 3 patients). Genotyping of CYP3A5 and CYP2C19 in renal transplantation should be considered to be of interest when treating with tacrolimus and omeprazole, because CYP2C19*2/*2 variant indirectly elicits an increase of tacrolimus blood levels and, in our study population, the adverse effects described.

Early statin use is an independent predictor of long-term graft survival

Background. Statin use in renal transplantation has been associated with a lower risk of patient death but not with an improvement of graft functional survival. The aim of this study is to evaluate the effect of statin use in graft survival, death-censored graft survival and patient survival using the data recorded on the Spanish Late Allograft Dysfunction Study Group. Patients and methods. Patients receiving a renal allograft in Spain in 1990, 1994, 1998 and 2002 were considered. Since the mean follow-up in the 2002 cohort was 3 years, statin use was analysed considering its introduction during the first year or during the initial 2 years after transplantation. Univariate and multivariate Cox regression analyses with a propensity score for statin use were employed to analyse graft survival, death-censored graft survival and patient survival. Results. In the 4682 evaluated patients, the early statin use after transplantation significantly increased from 1990 to 2002 (12.7%, 27.9%, 47.7% and 53.0%, P < 0.001). Statin use during the first year was not associated with graft or patient survival. Statin use during the initial 2 years was associated with a lower risk of graft failure (relative risk [RR] = 0.741 and 95% confidence interval [CI] = 0.635–0.866, P < 0.001) and patient death (RR = 0.806 and 95% CI = 0.656–0.989, P = 0.039). Death-censored graft survival was not associated with statin use during the initial 2 years. Conclusion. The early introduction of statin treatment after transplantation is associated with a significant decrease in late graft failure due to a risk reduction in patient death.

Pharmacogenetics of Immunosuppressive Drugs in Renal Transplantation

Still, there is no ideal solution to many of the diseases faced by health professionals in daily clinical practice, so we still have to look for alternatives to the established treatments. The idea of a targeted and personalized therapy to achieve therapeutic success is a goal that is getting more and more important every day. In this context there arises the concept of personalized medicine which is related in our case to the genetic variability associated with different individual response to the same treatment. That is, there is a difference in the response to the same drug in different patients that appears to be related to the different versions of each patients genes coding for transport proteins, for enzymes involved in metabolism and those genes responsible for the drug mechanism of action, all necessary for the drug to perform its therapeutic effect. This kind of research is developed by two disciplines: pharmacogenetics and pharmacogenomics. These two terms are often mixed and difficult to distinguish, so the international regulatory organizations have tried to fix the proper definitions of both terms. The European Medicines Agency shows the definitions on its web site (www.ema.europa.eu, EMEA/CHMP/ICH/437986/2006) where according to the the International Conference on Harmonisation (ICH), Pharmacogenomics is defined as the study of variations of DNA and RNA characteristics as related to drug response, while Pharmacogenetics is a subset of pharmacogenomics and is defined as the study of variations in DNA sequence as related to drug response.

Renal Transplantation Recipients with AA Genotype in SNP rs4244285 of CYP2C19 Show An Increase in Hospital Stay Duration and Allograft Dysfunction Probably Due to Increased Tacrolimus Levels Caused by Interaction with Omeprazol: 1624

Bosó V.1, Herrero M.J.1, Bea S.2, Galiana M.3, Marrero P.3, Marqués M.3, Sánchez-Plumed J.2, Hernández J.2, Poveda J.L.3, Aliño S.F.4,5 1Instituto Investigacion Sanitaria La Fe, Unidad de Farmacogenetica, Valencia, Spain, 2Hospital Universitario y Politécnico La Fe, Servicio Nefrología, Valencia, Spain, 3Hospital Universitario y Politécnico La Fe, Servicio Farmacia, Valencia, Spain, 4Hospital Universitario y Politécnico La Fe, Unidad de Farmacogenética, Valencia, Spain, 5Universidad de Valencia, Farmacología, Valencia, Spain