Search

Background: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics., Methods: 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC 0-12h and AUC 12-24h (for Tac BID), or AUC 0-24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC 0-24h and the AUC-to-trough concentration ratios., Results: The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC 0-24h was significantly higher on D8 than at M3. The AUC 0-24h /C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10 -5 ). In contrast, both the post-transplantation period (p=1.53×10 -4 ), and CYP3A5 expression (p=0.003) had a significant influence on the AUC 0-24h /C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC 0-24h was better correlated with C24h than C0, and for Tac-BID the AUC 0-12h was better correlated with C12h than C0., Conclusions: This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined 'trough level') is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC 0-24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC 0-12h for TAC BID and AUC 0-24h for TAC OD is feasible using only 3 time points within the first 3h, thus giving access to the actual overall exposure., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C 0 ) >3 μg/L; group B had no change in TacER dose (TacER C 0 7-12 μg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C 0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 μg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 μg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C 0 should be maintained >7 μg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Any biochemical reaction underlying drug metabolism depends on individual gene-drug interactions and on groups of genes interacting together. Based on a high-throughput genetic approach, we sought to identify a set of covariant single-nucleotide polymorphisms predictive of interindividual tacrolimus (Tac) dose requirement variability. Tac blood concentrations (Tac C 0 ) of 229 kidney transplant recipients were repeatedly monitored after transplantation over 3 mo. Given the high dimension of the genomic data in comparison to the low number of observations and the high multicolinearity among the variables (gene variants), we developed an original predictive approach that integrates an ensemble variable-selection strategy to reinforce the stability of the variable-selection process and multivariate modeling. Our predictive models explained up to 70% of total variability in Tac C 0 per dose with a maximum of 44 gene variants (p-value <0.001 with a permutation test). These models included molecular networks of drug metabolism with oxidoreductase activities and the multidrug-resistant ABCC8 transporter, which was found in the most stringent model. Finally, we identified an intronic variant of the gene encoding SLC28A3, a drug transporter, as a key gene involved in Tac metabolism, and we confirmed it in an independent validation cohort., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Adherence to immunosuppressive treatments is a major concern in transplanted patients., Methods: This 6-month French observational, longitudinal, prospective study aimed to assess patient adherence to and acceptance of once-daily tacrolimus (Advagraf) initiation in kidney and liver transplant recipients. Data from 1106 patients initiating once-daily tacrolimus during posttransplant follow-up were analyzed. Adherence and acceptance were assessed using self-administered questionnaires at inclusion and at 3 and 6 months., Results: Mean age was 52.4 ± 13.2 years, 61.5% were men. For 94.9% of patients, once-daily tacrolimus was prescribed after switching from twice-daily tacrolimus. At inclusion, 20.9% of patients reported good treatment adherence, 72.0% minor nonadherence, and 7.1% were nonadherent. Mean general acceptance score (range, 0-100) was 77.7 (±24.7). At 3 months, adherence was improved in 21.1%, unchanged in 69.2%, and worsened in 9.7% of patients. Mean general acceptance score was 75.4 (±26.5). General acceptance score was improved in 28.0%, unchanged in 39.4%, and worsened in 32.7% of patients. At 6 months, similar changes in adherence and acceptance were observed. Higher general acceptance score at month 3 was significantly associated with better adherence at month 6., Conclusions: Conversion to once-daily tacrolimus led to an improved rate of adherence at month 3 in more than 20% of patients and a worsened rate of adherence in less than 10% of patients.

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: POR*28 is a recently newly described allelic variant of the cytochrome P450 oxidoreductase (POR), which might be associated with an increased metabolic activity of P450 cytochromes (CYP) 3A5 and 3A4. Consequently, carriers of at least 1 allele of this polymorphism could require increased calcineurin inhibitors doses to reach the target residual concentrations (C0). The objective of this study was to test whether the allelic variant of POR, which is associated with an increased metabolic activity of CYP3A, impacts tacrolimus (Tac) pharmacokinetics., Methods: We tested this hypothesis in a population of 229 kidney transplant recipients (KTR) from a large, multicenter, prospective and randomized study. We have analyzed the association between POR*28 genotype and the proportion of individuals reaching the target Tac residual concentration (Tac C0) 10 days after transplantation. We have also measured the association between POR*28 and the Tac C0, and adjusted Tac C0 (Tac C0/Tac dose) over time using generalized mixed linear models., Results: Ten days after transplantation, there was no difference of frequencies of KTR within the target range of Tac C0 (C0 10-15 ng/mL) according to the POR*28 genotype (P = 0.8). The mean Tac C0 at day 10 in the POR*1/*1 group was 15.3 ± 9.7 ng/mL compared with 15.7 ± 7.8 ng/mL in the POR*1/*28 group and 14.2 ± 6.8 ng/mL, in the POR*28/*28 group, P = 0.8. The adjusted Tac C0 was not associated with POR*28 genotype over time (random effects model, P = 0.9). When restricted to KTR expressing CYP3A5, POR*28 genotype did not impact the proportion of individuals within the Tac C0 target range neither the adjusted Tac C0 (random effects model, P = 0.1)., Conclusions: POR*28 does not significantly influence Tac pharmacokinetic parameters in a large cohort of KTR. This study does not confirm recent findings indicating that POR*28 carriers require more Tac to reach target C0.

CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C(0)). The aim of this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C(0). Secondary end points included the number of dose modifications and the delay in achieving the targeted C(0). In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C(0) at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C(0) was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C(0). Whether this improvement will affect clinical outcomes requires further evaluation.

In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.

The promises of pharmacogenetics are to elucidate the inherited basis of differences between individual responses to drugs in order to identify the right drug and dose for each patient. The recent identification of genetic polymorphisms in drug-metabolizing enzymes and drug transporters led to the hypothesis that genetic factors may be implicated in the interindividual variability of the pharmacokinetic or pharmacodynamic characteristics of immunosuppressive drugs, major side effects, and efficacy. The purpose of this study was to provide a short overview of recent results obtained in the field of pharmacogenetics of tacrolimus and sirolimus, both substrates of the cytochrome P450 3A (CYP3A) enzymes and of the efflux pump P-glycoprotein, the product of the Multidrug Resistance-1 (MDR1) genes. A number of retrospective studies that demonstrated a link between the polymorphisms governing the CYP3A5 protein expression, with more conflicting results with the MDR1 gene polymorphisms, related to the daily dose necessary to achieve adequate blood tacrolimus levels. The CYP3A5 polymorphisms have also been associated with sirolimus pharmacokinetics. One challenge is to investigate the combined effect of a number of different polymorphisms in various genes to define genetic backgrounds with different pharmacokinetic profiles using high throughput technologies. Another challenge is to move toward prospective randomized studies to explore whether a pharmacogenetic approach, taking into account a limited number of polymorphisms prior to drug treatment, could be used on an individual basis to guide initial dosing of a given drug. The last challenge is based on "target" pharmacogenetics to investigate the role of the polymorphisms of other genes implicated in the efficacy and/or safety of the drug.

Background: Immunosuppressive drugs given to solid organ transplant recipients may be responsible for cosmetic side effects which can endanger patient compliance. Cyclosporine is associated with hirsutism whereas tacrolimus has been associated with rare cases of alopecia. Since 1998, we have included tacrolimus within the immunosuppressive regimen following kidney-pancreas transplantation. The aim of this study was to evaluate the incidence of alopecia in this population and possible risk factors., Methods: Between January 1, 1995 and October 31, 2003, 59 consecutive simultaneous kidney-pancreas (SPK) transplants were performed in 58 recipients (27 females and 31 males). The immunosuppressive regimen comprised corticosteroids, calcineurin inhibitor (cyclosporine, n=11; or tacrolimus, n=40) and a purine inhibitor (azathioprine or mycophenolate mofetil)., Results: Clinically significant alopecia occurred in 13 patients (28.9%) receiving tacrolimus versus none receiving cyclosporine (P<0.001). Of those who experienced alopecia, 11 were female and two were male (P=0.02). The mean delay between transplantation and alopecia was 422 days (range 100-1,567). Other causes of alopecia were excluded. Treatment of alopecia with topic minoxidil was successful in all cases but one, which required conversion from tacrolimus to cyclosporine., Conclusions: Alopecia is a frequent complication in women receiving tacrolimus therapy following SPK transplantation. Its pathogenesis is unknown. This cosmetic complication must be discussed with patients before transplantation to minimize the risk of noncompliance.

Background: Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation., Methods: We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment., Results: The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level., Conclusions: We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.

Background: Tacrolimus pharmacokinetic characteristics vary greatly among individuals. Tacrolimus is a substrate of cytochrome p450 (CYP), of subfamily CYP3A. CYP3A activity is the sum of the activities of the family of CYP3A genes, including CYP3A5. Subjects with the CYP3A5*1/*1 genotype express large amounts of CYP3A5. Heterozygotes (genotype CYP3A5*1/*3) also express the enzyme. We postulated that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations., Methods: CYP3A5 genotype was evaluated in 80 renal transplant recipients and correlated with the daily tacrolimus dose and concentration-to-dose ratio., Results: The frequency of the homozygous CYP3A5*1 genotype (CYP3A5*1/*1) was 5%, and 11% of subjects were heterozygous (CYP3A5*1/*3). The mean doses required to obtain the targeted concentration-to-dose ratio were significantly lower in patients with the CYP3A5*1/*1 genotype., Conclusions: Determination of CYP3A5 genotype is predictive of the dose of tacrolimus in renal transplant recipients and may help to determine the initial daily dose needed by individual patients for adequate immunosuppression without excess nephrotoxicity.

The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.