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ABSTRACT: OBJECTIVE: P450 oxidoreductase (POR) is essential for cytochrome P450 (CYP) activity in humans. The POR*28 allele (A503V) has been shown to impact on in-vitro CYP-mediated metabolism, including CYP3A isoenzymes. The aim of the present study was to determine the in-vivo impact of the POR*28 allele on the pharmacokinetics of the classic CYP3A phenotyping probes midazolam and erythromycin. Whereas midazolam is metabolized by both CYP3A4 and CYP3A5, erythromycin is exclusively oxidized by CYP3A4. MATERIALS AND METHODS: To assess CYP3A activity, 108 cancer patients received midazolam and 45 others underwent the erythromycin breath test. Patients were genotyped for POR*28, CYP3A4*22 and CYP3A5*3. RESULTS: In patients expressing CYP3A5, POR*28 carriers showed 45% lower midazolam metabolic ratios compared with POR*1/*1 patients (P<0.001). This is in line with a lower CYP3A5 activity toward midazolam for POR*28 carriers. In CYP3A5 nonexpressers, POR*28 had no influence on midazolam pharmacokinetics. For erythromycin, POR*28 carriership did not influence its metabolism. CONCLUSION: Our data show that the POR*28 allele is associated with a lower in-vivo CYP3A5 activity, but has no effects on CYP3A4-mediated erythromycin and midazolam metabolism.
Pharmacogenetics and Genomics 01/2013; · 3.48 Impact Factor
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ABSTRACT: Many studies have attempted to explain the interindividual variability observed in drug metabolism by assessing the impact of SNPs in genes implicated in drug absorption, distribution, metabolism and excretion pathways. Particular attention has been paid to the CYP450s. CYP3A4 is the main CYP isoform in human liver and intestine and is involved in the metabolism of many drugs. Its activity, however, is characterized by widespread variation in the general population, which is thought to have a genetic basis. A new CYP3A4 allele (CYP3A4*22; rs35599367 C>T in intron 6) with a frequency of 5-7% in the Caucasian population was recently discovered through its association with low hepatic CYP3A4 expression and CYP3A4 activity, and showing effects on statin, tacrolimus and cyclosporine metabolism. This review will summarize the current literature on phenotypes linked to this new promising CYP3A4 genetic marker SNP and discusses the potential clinical relevance.
Pharmacogenomics 01/2013; 14(1):47-62. · 3.97 Impact Factor
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ABSTRACT: Every month, new releases on the relationship between pharmacogenetic biomarkers and immunosuppressive drug therapy in kidney transplantation are published. However, the systematic clinical application of these discoveries occurs at a very slow pace, and the usefulness of knowing a patient's genotype remains an important matter of debate. This can be partially ascribed to the lack of consistency when looking at the different associations reported across several studies but also the need for a broad-spectrum view and a rigorous analysis of the relevance of the different associations observed to date. For that purpose, we performed a comprehensive analysis of the strength of the different reported genetic associations, and in this article we discuss their potential for clinical implementation in kidney transplantation. For tacrolimus, it is likely that a genotype-based drug dosage can benefit patient outcome, while for ciclosporin A, the data appear less convincing. For the mammalian target of rapamycin inhibitors, sirolimus and everolimus - given the lack of data and the absence of large prospective studies - it is premature to implement pharmacogenetics, but some novel and promising leads have recently been reported. For mycophenolate mofetil, the complex metabolic pathways of its active moiety, mycophenolic acid, complicate analysis of the various published associations. However, at present, some interesting findings can be highlighted and offer potential value to assist clinicians in decision making.
Molecular diagnosis & therapy 11/2012; · 1.71 Impact Factor
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ABSTRACT: The cytochrome P450 (CYP) 3A4*22 allelic status influences the pharmacokinetics of tacrolimus independently of an individual's CYP3A5 genotype. In their recent publication, Passey et al described an algorithm that predicts tacrolimus apparent clearance (CL/F) by taking into account the age and CYP3A5 genotype of a patient, time after kidney transplantation, whether the transplantation was performed at a steroid-sparing center or not and whether the patient was treated with a calcium channel blocker (CCB). However, as the effect of the CYP3A4*22 allele was only recently reported, these authors did not consider this variable as a potential predictive factor for tacrolimus CL/F.
British Journal of Clinical Pharmacology 11/2012; · 2.96 Impact Factor
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ABSTRACT: High intra-patient variability in TCL exposure is a risk factor for allograft loss and late acute rejection. We hypothesized that a higher intra-patient variability leads to a faster decline in GFR in pediatric renal transplant patients and that adolescents have a higher intra-patient variability due to poorer adherence. We included 69 children aged 3.5-18 yr who had undergone renal transplantation between April 1996 and May 2009 in two pediatric nephrology centers in the Netherlands. We analyzed TCL trough concentrations over a period of one yr and calculated TCL trough concentrations variability using VC. We investigated the correlation between the TCL trough concentrations variability and the decline in estimated GFR over four yr. The median intra-patient variability in TCL concentrations was 30.1% (range 8.6-77.6) and the mean GFR slope -3.8 mL/min/1.73 m(2) /yr. The VC correlated neither with the GFR slope, nor with the patients' age. However, children with late acute rejection had higher VC (p = 0.045). We were unable to provide evidence that a high variability in TCL exposure leads to a faster decline in renal function, although children with late acute rejection have a higher variability in TCL exposure. Adolescents do not have a higher intra-patient variability in TCL trough concentrations than younger children.
Pediatric Transplantation 06/2012; 16(6):613-8. · 1.48 Impact Factor
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Transplantation 05/2012; 93(10):e39-40; author reply e41-2. · 4.00 Impact Factor
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ABSTRACT: Cyclosporine A (CsA) is a substrate of cytochrome P450 3A4 (CYP3A4). Recently, a newly discovered intron 6 single-nucleotide polymorphism in CYP3A4 (rs35599367 C>T), defining the CYP3A4*22 allele, has been linked to reduced hepatic expression and activity of CYP3A4. In the present study, the clinical impact of this single-nucleotide polymorphism was investigated in a cohort of patients receiving a CsA-based immunosuppressive regimen.
A total of 172 de-novo kidney transplant recipients, receiving CsA/mycophenolate mofetil as immunosuppressive therapy and participating in the Fixed-Dose Concentration Controlled study, were genotyped for the new CYP3A4*22 allele. CsA C(0) and/or C(2) levels were measured on days 3 and 10 and in months 1, 3, 6, and 12 after transplantation. Plasma creatinine concentrations, delayed graft function (DGF), and biopsy-proven acute rejection were recorded.
The CYP3A4*22 allele was significantly associated with a higher risk of DGF compared with the CYP3A4*1/*1 patients after adjustment for known risk factors [odds ratio (OR)=6.34, confidence interval (CI(95%): 1.38-29.3), P=0.015]. Mixed-model analysis demonstrated that the overall creatinine clearance was 20% lower in CYP3A4*22 allele carriers compared with CYP3A4*1/*1 patients [CI(95%) (-33.1 to -7.2%), P=0.002]. For ABCB1 3435C>T, T-variant carriers had a decreased risk of developing DGF compared with CC patients [CT: OR=0.30, CI(95%) (0.11-0.77), P=0.011; TT: OR=0.18, CI(95%) (0.05-0.67), P=0.011].
CYP3A4*22 constitutes a risk factor for DGF and worse creatinine clearance in patients receiving CsA-based immunosuppressive therapy. Therefore, pretransplant genotyping for the CYP3A4*22 allele might help clinicians to identify patients at risk of DGF and poor renal function when treated with CsA.
Pharmacogenetics and Genomics 02/2012; 22(5):373-80. · 3.48 Impact Factor
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ABSTRACT: Therapeutic drug monitoring is used to individualize cyclosporine A (CsA) dosing after transplantation. However, immunosuppressant concentrations within the graft may better predict clinical outcomes, including toxicity. This study aimed to develop a method suitable for CsA measurement using routine fine-needle biopsy samples. CsA was quantified retrospectively in kidney and liver tissues from 10 rats administered CsA, and 21 core needle kidney biopsies taken from renal transplant patients with suspected graft dysfunction. Dried biopsies were weighed (mean ± SD weights of 0.22 ± 0.18 mg), enzymatically solubilized, and then CsA was extracted and quantified using online 2-dimensional liquid chromatography-tandem mass spectrometry. The method was linear (r² > 0.997, n = 10), accurate, and precise (quality control and calibrator coefficient of variation and bias <15%), with minimal matrix effects (coefficient of variation and bias <15%). Reproducibility of tissue weight measurements was confirmed by retrospective DNA quantitation, with a significant linear correlation between weight and total DNA concentration (r² = 0.988). In rats, there was a significant linear correlation between CsA concentrations in liver and kidney tissues (r² = 0.996) but there was no correlation between blood (C0) and tissue CsA concentrations (Spearman r = 0.430 and 0.503, P > 0.05). Similarly, in 16 transplant patients, for whom blood CsA concentrations (C2) were available within 1 day of the renal biopsy being performed, there was no significant correlation between CsA concentrations in blood and kidney tissue (Spearman r = 0.168, P > 0.05). In situ CsA measurements acquired using this method could make an easy transition into clinical use due to their retrospective nature and minimal disruption to current clinical protocols and could provide an additional tool for optimizing clinical outcomes in the future.
Therapeutic drug monitoring 12/2011; 33(6):688-93. · 2.43 Impact Factor
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ABSTRACT: Immunosuppressive drugs used in organ transplantation are highly effective in preventing acute rejection. However, the clinical use of these drugs is complicated by the fact that they display highly variable pharmacokinetics and pharmacodynamics between individual patients. The influence of genetic variation on the interindividual variability in immunosuppressive drug disposition, efficacy, and toxicity has been explored in recent years. The polymorphically-expressed ATP-binding cassette (ABC) transporter proteins, in particular ABCB1 and ABCC2, have been investigated extensively because they play an important role in the absorption, distribution and elimination of many immunosuppressive drugs in use today. From these studies it can be concluded that polymorphisms in ABCB1 and ABCC2 have no consistent effect on immunosuppressant pharmacokinetics and toxicity although polymorphisms in ABCB1 appear to be related to the risk of developing calcineurin inhibitor-related nephrotoxicity. However, the latter needs to be replicated before an individual's ABCB1 genotype can become a useful marker that is applied in clinical practice. Future studies evaluating the influence of ABC transporter gene polymorphisms should explore the relationship with intracellular rather than systemic drug concentrations further in well-designed clinical studies. Until then, single-nucleotide polymorphisms in ABC transporter genes are not suitable to act as biomarkers for solid organ transplantation.
Clinica chimica acta; international journal of clinical chemistry 10/2011; 413(17-18):1326-37. · 2.54 Impact Factor
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ABSTRACT: Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes.
We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study).
The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, -46% to -20%; P = 0.018). When combined with the *3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A5*3/*3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A5*3/*3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A5*1 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A5*3/*3 (P < 0.001), +101% for CYP3A4 CC homozygotes with CYP3A5*3/*3 (P < 0.001), and +64% for CYP3A4 T allele carriers with CYP3A5*1 (P = 0.020),compared with CYP3A4 CC homozygotes with CYP3A5*1.
The CYP3A4 rs35599367C>T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.
Clinical Chemistry 09/2011; 57(11):1574-83. · 7.91 Impact Factor
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ABSTRACT: We investigated the association between genetic polymorphisms in ABCB1 and SLCO1B and mycophenolic acid (MPA) pharmacokinetics, and MPA-related diarrhea and leukopenia in 338 kidney transplant recipients.
A total of 338 patients participating in an international, randomized-controlled clinical trial were genotyped for ABCB1 and SLCO1B. Patients were all treated with mycophenolate mofetil and either cyclosporine or tacrolimus. MPA-area under the curve (AUCs), MPA-glucuronide AUCs and acylglucuronide-AUCs were measured on days 3 and 10, and months 1, 3, 6, and 12 after kidney transplantation.
The risk of developing diarrhea was 1.8-fold higher in patients cotreated with tacrolimus compared with patients cotreated with cyclosporine (95% confidence interval: 1.03-3.13; P=0.038). ABCB1 and SLCO1B SNPs were not associated with dose-adjusted exposure to MPA, MPA-glucuronide, nor acylglucuronide-MPA nor with the incidence of diarrhea or leukopenia.
Genotyping for ABCB1 or SLCO1B pretransplantation is unlikely to be of clinical value for individualization of MPA therapy.
Pharmacogenetics and Genomics 08/2011; 22(6):399-407. · 3.48 Impact Factor
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ABSTRACT: In view of future pharmacokinetic studies, a highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous quantification of tamoxifen and three of its main phase I metabolites in human lithium heparinized plasma. The analytical method has been thoroughly validated in agreement with FDA recommendations. Plasma samples of 200 μl were purified by liquid-liquid extraction with 1 ml n-hexane/isopropanol, after deproteination through addition of 50 μl acetone and 50 μl deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC(®) BEH C18 1.7 μm 2.1 mm×100 mm column eluted at a flow-rate of 0.300 ml/min on a gradient of 0.2mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10 min, with elution times of 2.9, 3.0, 4.1 and 4.2 min for endoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and tamoxifen, respectively. Tamoxifen and its metabolites were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. The multiple reaction monitoring transitions were set at 372>72 (m/z) for tamoxifen, 358>58 (m/z) for N-desmethyl-tamoxifen, 388>72 (m/z) for 4-hydroxy-tamoxifen and 374>58 (m/z) for endoxifen. The analytical method was highly sensitive with the lower limit of quantification validated at 5.00 nM for tamoxifen and N-desmethyl-tamoxifen and 0.500 nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187 ng/ml for tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen, respectively. The method was also precise and accurate, with within-run and between-run precisions within 12.0% and accuracy ranging from 89.5 to 105.3%. The method has been applied to samples from a clinical study and cross-validated with a validated LC-MS/MS method in serum.
Journal of pharmaceutical and biomedical analysis 08/2011; 56(5):1016-23. · 2.45 Impact Factor
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ABSTRACT: The most common immunosuppressive treatment in de novo renal transplantation is a triple regimen that includes tacrolimus, mycophenolate mofetil (MMF) and corticosteroids, and that may also include antibody induction. Whether nephrotoxicity is an issue with tacrolimus at the currently used dosages remains an open question.
We pooled data from three large, randomized, de novo renal transplantation studies (Symphony, Fixed Dose Concentration Controlled [FDCC], and OptiCept) that used variations of the triple regimen with respect to tacrolimus target levels, MMF dosing, and antibody induction. We used multivariate linear regression to explore the relationship of renal function at 1 year after transplantation (estimated glomerular filtration rate) with tacrolimus levels and MMF dose measured over the previous 6 months. The model included also a series of possible confounders. RESULTS.: The analysis population consisted of 998 patients. On average, tacrolimus levels were in a range considered low (mean ± standard deviation 7.2 ± 2.54 ng/mL), and MMF dose was 1.5 ± 0.61 g/day. Lower tacrolimus levels and higher MMF doses were associated with significantly better renal function. There were other variables associated with renal function, most notably acute rejection, donor age, and delayed graft function. Subanalyses in each of the three studies gave a consistent picture. There was no overt difference in the effect sizes when patients with stage II (estimated glomerular filtration rate 60-89 mL/min) or stage III (30-59 mL/min) chronic kidney disease were assessed separately.
Tacrolimus seems to have a moderate but consistent nephrotoxic effect even in modern efficient immunosuppressive regimens where it is used at lower doses than in previous years.
Transplantation 07/2011; 92(1):82-7. · 4.00 Impact Factor
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ABSTRACT: The risk of long-term chronic allograft nephropathy and graft loss after kidney transplantation is increased in patients with a high intrapatient variability of tacrolimus (Tac) clearance.
To test whether this intrapatient variability is associated with an individual's CYP3A5 genotype, we measured the intrapatient variability in Tac clearance in a cohort of 208 kidney transplant recipients treated with Tac and mycophenolate mofetil.
Tac dose requirement was significantly higher in patients expressing CYP3A5. However, intraindividual variability of Tac clearance was not related to CYP3A5 genotype.
Intraindividual variability in Tac clearance is not related to CYP3A5 genotype. Other factors, including patient adherence, may explain the variability in Tac clearance within an individual patient over time.
Therapeutic drug monitoring 06/2011; 33(3):369-71. · 2.43 Impact Factor
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Yannick Le Meur,
Richard Borrows,
Mark D Pescovitz,
Klemens Budde,
Josep Grinyo,
Roy Bloom,
Robert Gaston,
Rowan G Walker,
Dirk Kuypers, Teun van Gelder,
Bryce Kiberd
Transplantation reviews (Orlando, Fla.) 03/2011; 25(2):58-64.
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ABSTRACT: Assessing the value of mycophenolic acid (MPA) monitoring outside renal transplantation is hindered by the absence of any trial comparing fixed-dose and concentration-controlled therapy. However, in liver and thoracic transplantation particularly, clinical trials, observational studies with comparison groups, and case series have described MPA efficacy, exposure/efficacy relationships, pharmacokinetic variability, and clinical outcomes relating to plasma MPA concentrations. On the basis of this evidence, this report identifies MPA as an immunosuppressant for which the combination of variable disposition, efficacy, and adverse effects contributes to interindividual differences seemingly in excess of those optimal for a fixed-dosage mycophenolate regimen. Combined with experiences of MPA monitoring in other transplant indications, the data have been rationalized to define circumstances in which measurement of MPA concentrations can contribute to improved management of mycophenolate therapy in nonrenal transplant recipients.
Transplantation reviews (Orlando, Fla.) 03/2011; 25(2):65-77.
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Burkhard Tönshoff,
Elias David-Neto,
Robert Ettenger,
Guido Filler, Teun van Gelder,
Jens Goebel,
Dirk R J Kuypers,
Eileen Tsai,
Alexander A Vinks,
Lutz T Weber,
Lothar Bernd Zimmerhackl
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ABSTRACT: Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppressive therapy in pediatric renal and heart transplant recipients. Children undergo developmental changes (ontogeny) of drug disposition, which may affect drug metabolism of the active compound mycophenolic acid (MPA). Therefore, a detailed characterization of MPA pharmacokinetics and pharmacodynamics in this patient population is required. In general, the overall efficacy and tolerability of MMF in pediatric patients appear to be comparable with those in adults, except for a higher prevalence of gastrointestinal adverse effects in children younger than 6 years. The currently recommended dose in pediatric patients with concomitant cyclosporine is 1200 mg/m(2) per day in 2 divided doses; the recommended MMF dose with concomitant tacrolimus or without a concurrent calcineurin inhibitor is 900 mg/m(2) per day in 2 divided doses. Recent data suggest that fixed MMF dosing results in MPA underexposure (MPA-area under the concentration-time curve (AUC(0-12)), <30 mg × h/L) early posttransplant in approximately 60% of patients. To achieve adequate MPA exposure in most patients, an initial MMF dose of 1800 mg/m(2) per day with concomitant cyclosporine and 1200 mg/m(2) per day with concomitant tacrolimus for the first 2 to 4 weeks posttransplant has been suggested. As in adults, there is an approximately 10-fold variability in dose-normalized MPA-AUC(0-12) values between pediatric patients after renal transplantation, strengthening the argument for concentration-controlled dosing of the drug. Although the clinical utility of therapeutic drug monitoring of MPA for graft outcome and patient survival is still controversial, potential indications are the avoidance of underimmunosuppression, particularly in patients with high immunologic risk in the initial period posttransplant, in patients who are treated with protocols that explore the possibilities of calcineurin inhibitor minimization, withdrawal or even complete avoidance, and steroid withdrawal or avoidance regimens that might also benefit from intensified therapeutic drug monitoring of MPA. An additional indication especially in adolescent patients is the monitoring of drug adherence. Therapeutic drug monitoring of MPA in pediatric solid organ transplantation using limited sampling strategies is preferable over drug dosing based on trough level monitoring only. Several validated pediatric limited sampling strategies are available. Clearly, more research is required to determine whether pediatric patients will benefit from therapeutic drug monitoring of MPA for long-term maintenance immunosuppression with MMF.
Transplantation reviews (Orlando, Fla.) 03/2011; 25(2):78-89.
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ABSTRACT: Mycophenolic acid (MPA) plasma concentrations are highly variable on standard-dose mycophenolate mofetil therapy. At creatinine clearances below 25 mL/min, MPA clearance increases as a result of a higher nonprotein-bound fraction. Patients with delayed graft function (DGF) after renal transplantation are exposed to low total MPA concentrations, when risk of rejection is highest. This study investigated the influence of DGF on MPA exposure and on clinical outcome.
Adult renal transplantation patients treated with mycophenolate mofetil, corticosteroids, and either microemulsified cyclosporine (n = 459) or tacrolimus (n = 371) participated in a randomized controlled trial (the Fixed-Dose Concentration-Controlled [FDCC] Study). Abbreviated MPA areas under the curve (AUCs) were obtained on Day 3, Day 10, Week 4, and Month 3, to calculate MPA AUC₀₋₁₂. Free MPA AUC values were available for a subgroup of patients (n = 269).
The overall incidence of DGF was 187 of 830 (23%) and did not differ between cyclosporine-treated (24%) and tacrolimus- (21%) treated patients. The incidence of biopsy-proven acute rejection at 12 months was significantly higher in patients with DGF (13.8% versus 21.4%). Patients with DGF had significantly lower dose-corrected MPA AUC on Day 3 and Day 10. Free MPA fraction and dose-corrected free MPA AUC were significantly higher in patients with DGF, from Day 3 until Month 3. The total number of patients with at least one opportunistic infection was significantly higher in patients with DGF (33.2%) compared with patients without DGF (25.8%) (P = 0.048). Patients with DGF developing opportunistic infections did not have higher total MPA AUC nor higher free MPA AUC compared with those without opportunistic infections.
Patients with DGF have significantly lower dose-corrected MPA AUC in the first month after renal transplantation, presumably as a result of enhanced MPA clearance on account of the elevated MPA free fraction. Because patients with DGF have a higher rate of acute rejection and lower MPA exposure, higher dosing of mycophenolate mofetil in such patients may improve outcome. However, the already increased incidence of opportunistic infections in patients with DGF is a concern.
Therapeutic drug monitoring 03/2011; 33(2):155-64. · 2.43 Impact Factor
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ABSTRACT: Mycophenolate mofetil (MMF) is widely used for immunosuppressive therapy in renal transplantation, but comparative data regarding efficacy and safety in paediatric vs. adult kidney allograft recipients in one and the same study are lacking.
We therefore performed this subgroup analysis of the FDCC trial, a 12-month, prospective, randomised study, comparing fixed-dose (FD) with concentration-controlled (CC) MMF dosing in paediatric and adult renal transplant recipients. Sixty-two paediatric and 839 adult de novo patients in 19 countries were randomised 1:1 to receive fixed-dose or concentration-controlled MMF therapy in combination with calcineurin inhibitors and corticosteroids.
Both patient and allograft survival proved to be excellent in paediatric patients (98.4% and 90.3%) and adults (96.8% and 95.0%). The rates of biopsy-proven acute rejections (BPAR) and treated acute rejection episodes (ARE) were comparable between paediatric (12.9% and 17.7%) and adult patients (15.5% and 20.7%). Transplant function at 12 months post-transplant was similar in paediatric (67.8 ± 45.6 mL/min/1.73 m2;) and adult recipients (64.7 ± 23.3 mL/min/1.73 m2;). Children < 6 years (n = 10) exhibited a numerically higher frequency of leucocytopaenia (20%), diarrhoea (40%) and weight loss (10%) than older children (6-18 years; 5.8%, 28.8% and 1.9%) and adults (16.1%, 24.7% and 1.5%). On the whole, the percentage of patients who experienced adverse events causing interruption of MMF therapy were numerically lower in children (4.8%) than in adults (12.5%). Conclusions. The overall efficacy and tolerability of MMF appear to be comparable between paediatric and adult patients. Further studies are needed to validate these results.
Nephrology Dialysis Transplantation 03/2011; 26(3):1073-9. · 3.40 Impact Factor
