Initial Tacrolimus Dose Research Articles

Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation

Background Dosage quantities of tacrolimus (TAC) vary according to cytochrome P450 3A5 (CYP3A5) genotype. Genotyping is expected to optimize the response to TAC response and to minimize adverse effects. In Thailand, kidney transplantation is reimbursable with the same diagnosis-related group payment regardless of patient's CYP3A5 genotype. Objective This study aimed to determine the costs of TAC administration, therapeutic drug monitoring (TDM), and hospitalization for kidney transplantation across CYP3A5*1/*1, *1/*3, and *3/*3 genotypes. Setting A single transplant center in a university hospital. Method This is an observational study that collected data from patients pooled from both arms of a randomized controlled trial that tested initial doses of TAC. Main outcome measure TAC and TDM cost and hospitalization cost for transplantation were compared between genotypes. Results The CYP3A5*1/*1 patients had the highest median combined TAC-TDM cost and hospitalization cost ($1062 and $9097), followed by CYP3A5*1/*3 ($859 and $6467) and CYP3A5*3/*3 patients ($761 and $5604). The CYP3A5*1/*1 patients had a higher hospitalization cost by $2787 over the CYP3A5*1/*3 patients, despite marginal significance. The CYP3A5*1/*1 patients had a significantly higher cost of TAC plus TDM (by $309) and hospitalization cost (by $3275) than the CYP3A5*3/*3 patients. Both study costs were significantly higher in patients with delayed graft functioning than in patients with instant or slow graft functioning. Conclusion The benefits of genotype detection in patients with CYP3A5*1/*1 should be considered for a higher reimbursement rate because of the substantial differences in total hospitalization cost for kidney transplantation among patients with different CYP3A5 genotypes.

Tacrolimus toxicity in organ transplantation: an overview

Tacrolimus is a macrolide lactone antibiotic, and acts as a calcineurin inhibitor. It is widely used to prevent organ transplant rejection. It has been approved as first-line treatment after organ transplantation. Tacrolimus has narrow therapeutic range and wide individual variability in its pharmacokinetics. In organ transplantation, immunosuppression is associated with important risks, in particular, related to infections and cardiovascular diseases, which are the predominant causes of death in those with a functioning graft. This review focuses on toxicity of tacrolimus after transplantation. Tacrolimus toxicity is a major determinant of morbidity and mortality in organ recipients after transplantation. Therefore, reducing toxicities has become a priority. To decrease the incidence of side effects, and expand graft survival, the appropriate initial and maintenance dose of tacrolimus is essential. Clinical conditions that influence tacrolimus pharmacokinetics, such as hemorrhage, systemic inflammation and shock, all result in higher variations of tacrolimus concentrations. In addition, unbound plasma concentration is a major important reasonable parameter for monitoring of receiving optimal tacrolimus dosing in the unstable patient. Therefore, the approach of tacrolimus monitoring is vital and will support to avoid tacrolimus toxicity in the early days after transplantation.

Precision Medicine for Tacrolimus Dosing in Heart Transplant Recipients

Interpatient variability in tacrolimus requirements are large and influenced by multiple factors including cytochrome P450 (CYP) genetics, specifically by CYP3A5 and to a lesser extent CYP3A4. Tacrolimus dosing tailored to CYP genotype has been shown to shorten time to therapeutic range in kidney transplant but data in heart transplant recipients is sparse and findings are variable. We recently implemented weight and genotype-based initial tacrolimus dosing in our heart transplant program. The objective of this study is to examine the impact of genetically tailored tacrolimus dosing on achieving therapeutic trough levels.

No Significant Influence of Reduced Initial Tacrolimus Dose on Risk of Underdosing and Early Graft Function in Older and Overweight Kidney Transplant Recipients

BackgroundNowadays, a reduced initial daily dose of tacrolimus (Tac) (0.1–0.15 mg/kg) is recommended for the majority of kidney transplant recipients (KTRs). The aim of the study was to analyze the safety of such a regimen, including the risk of first inadequately low Tac blood level, acute rejection (AR) occurrence, or early graft dysfunction. MethodsIn 2011, we introduced a modified (0.1–0.15 mg/kg/d) initial Tac dosing regimen in older (>55 years) and/or overweight KTRs. To assure the safety of this protocol, we monitored the risk of inadequately low blood Tac level (<6 ng/mL) and incidence of AR or delayed graft function (DGF). The historical cohort with the higher Tac dosing regimen (0.2 mg/kg/d, n = 208) served as a control group. ResultsThe mean Tac daily dose in 78 KTRs (group with reduced dosing) was 0.133 (95% confidence interval [CI], 0.130–0.136) mg/kg and was significantly lower than the standard, previously prescribed dose of 0.195 (95% CI, 0.194–0.197) mg/kg. Of note, induction therapy was employed twice more often in the reduced Tac dosing group. The dose reduction resulted in a slight, nonsignificant decrease in first Tac trough level. The percentages of patients with first Tac troughs <6 ng/mL (5.1% vs 4.8%), AR (6.4% vs 5.8%), and DGF (25.6% vs 31.2%) were similar in the reduced and standard dosing groups. ConclusionThe currently recommended reduction in Tac initial dosing does not increase the risk of inadequate immunosuppression and does not affect the early graft function. Regardless of Tac dose reduction, there is still a substantial risk of Tac overdosing in older or overweight KTRs.

Adequacy of Initial Everolimus Dose, With and Without Calcineurin Inhibitors, in Kidney Transplant Recipients.

This study investigates the adequacy of initial everolimus (EVR) dose, with and without calcineurin inhibitors (CNI), in kidney transplant recipients. This retrospective cohort analysis involved data from 305 kidney transplant recipients participating in 3 randomized trials receiving reduced dose cyclosporin A (CsA) combined with EVR 0.75 mg BID (CSA/EVR0.75, N = 32) or 1.5 mg BID (CSA/EVR1.5, N = 31), reduced dose tacrolimus (TAC) combined with EVR 1.5 mg BID (TAC0.05/EVR1.5, N = 83), standard dose TAC combined with EVR 1.5 mg BID (TAC0.1/EVR1.5, N = 93), and EVR 1.5 mg BID (EVR1.5, N = 66) with TAC introduction after day 5. The adequacy of the initial EVR dose, based on EVR whole blood trough between 3 and 8 ng/mL, was compared using first EVR blood concentrations obtained at day 3 after transplantation. Recipient age, proportion of patients with diabetes mellitus, and proportion of grafts from living donors were different among the groups. Dose-corrected EVR concentrations were higher in patients receiving CsA than in those receiving TAC or no calcineurin inhibitors (6.7 ± 5.9 versus 5.4 ± 2.2 versus 2.4 ± 0.8 versus 2.5 ± 0.9 versus 2.2 ± 0.7, P = 0.000). No differences were observed comparing dose adjusted EVR concentrations combined with TAC or alone (P = 0.073). The proportion of patients with EVR concentration below <3 ng/mL was lower when EVR was combined with CsA (25 versus 3 versus 43 versus 33 versus 50%, P = 0.000). Later introduction of TAC did not influence EVR concentrations. There were no differences in mean CsA concentrations comparing patients receiving EVR 0.75 or 1.5 mg BID (240 ± 143 versus 213 ± 105 ng/mL). On the other hand, mean TAC concentrations were higher according to the initial TAC dose regimen (6.4 ± 3.9 versus 9.8 ± 5.9 ng/mL). In de novo kidney transplant recipients, the choice of the initial dose of EVR should consider the type of calcineurin inhibitor to reach target EVR concentration within the first week in a higher proportion of patients, maximizing the efficacy/toxicity profile.

Which Kidney Transplant Recipients Can Benefit from the Initial Tacrolimus Dose Reduction?

Background Observational data suggest that the fixed initial recommended tacrolimus (Tc) dosing (0.2 mg/kg/day) results in supratherapeutic drug levels in some patients during the early posttransplant period. The aim of the study was to analyze a wide panel of patient-related factors and their interactions which increase the risk for first Tc blood level > 15 ng/ml. Materials and Methods We performed a retrospective analysis of 488 consecutive adult kidney transplant recipients who were initially treated with triple immunosuppressive regimen containing tacrolimus twice daily. The analysis included the first assessment of Tc trough blood levels and several demographic, anthropometric, laboratory, and comedication data. Results The multiple logistic regression analysis showed that age > 55 years, BMI > 24.6 kg/m2, blood hemoglobin concentration > 9.5 g/dl, and the presence of anti-HCV antibodies independently increased the risk for first Tc level > 15 ng/ml. The relative risk (RR) for first tacrolimus level > 15 ng/ml was 1.88 (95% CI 1.35–2.64, p < 0.001) for patients with one risk factor and 2.81 (2.02–3.89, p < 0.001) for patients with two risk factors. Conclusions Initial tacrolimus dose reduction should be considered in older, overweight, or obese kidney transplant recipients and in subjects with anti-HCV antibodies. Moreover, dose reduction of tacrolimus is especially important in patients with coexisting multiple risk factors.

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

Cytochrome P450 oxidoreductase (POR) is the only flavoprotein that donates electrons to all microsomal P450 enzymes (CYP), and several POR SNPs have been shown to be important contributors to altered CYP activity or CYP-mediated drug metabolism. In this study we examined the association between 6 POR SNPs and tacrolimus concentrations in Chinese renal transplant recipients. A total of 154 renal transplant recipients were enrolled. Genotyping of CYP3A5*3 and 6 POR SNPs was performed. All patients received a triple immunosuppressive regimen comprising tacrolimus, mycophenolate mofetil and prednisone. Dose-adjusted tacrolimus trough concentrations were obtained on d 7 (C0D7/D) after transplantation when steady-state concentration of tacrolimus was achieved (dosage had been unchanged for more than 3 d). Tacrolimus C0D7/D in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype carriers was 1.62- and 2.72-fold higher than those in CYP3A5*3/*3/ POR rs1057868-rs2868177 GC-GT diplotype non-carriers and CYP3A5*1 carriers (220.17±48.09 vs 135.69±6.86 and 80.84±5.27 ng/mL/mg/kg, respectively, P<0.0001). Of CYP3A5*3/*3/ POR rs1057868-rs2868177GC-GT diplotype carriers, 85.71% exceeded the upper limit of the target range (8 ng/mL), which was also significantly higher compared with the latter two groups (14.29% and 0.00%, respectively, P<0.0001). The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype explained 31.7% and 5.7%, respectively, of the inter-individual variability of tacrolimus C0D7/D, whereas the POR rs1057868-rs2868177 GC-GT diplotype could explain 10.9% of the inter-individual variability of tacrolimus C0D7/D in CYP3A5 non-expressers. The CYP3A5*3 and POR rs1057868-rs2868177 GC-GT diplotype accounted for the inter-individual variation of tacrolimus C0D7/D. Genotyping of POR rs1057868-rs2868177 diplotypes would help to differentiate initial tacrolimus dose requirements and to achieve early target C0 ranges in Chinese renal transplant recipients.

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.

Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.

Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype.

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.

Tacrolimus Metabolism and Risk of Acute Graft Versus Host Disease

Introduction: Tacrolimus is commonly used for prophylaxis of graft versus host disease (GVHD) after allogeneic hematopoietic cell transplant (HCT). Dosing strategies are weight-based, and trough levels are monitored for toxicity and efficacy. Tacrolimus metabolism is regulated by the CYP3A5 sub-family of the cytochrome P450 protein. Occurrence of the main single nucleotide polymorphism related to the functional variation of cytochrome P450 results in the absence of a functional CYP3A5 protein in patients who are homozygous carriers (CYP3A5*3/*3) versus patients with functional CYP3A5 (CYP3A5*1/*1 or CYP3A5*1/*3) [Niioka T et al, 2015]. Patients (pts) with the functional CYP3A5 protein metabolize tacrolimus rapidly; they require a higher drug dose to achieve the same therapeutic blood concentration compared to pts with the CYP3A5*1/*1 or *1/*3 genotypes [Rojas L et al, 2015; Terrazzino S et al, 2012]. We hypothesized that pts with *1/*1 or *1/*3 genotype (hyporesponders) will take a longer time to achieve therapeutic blood levels using weight-based dosing algorithms and potentially have an increased incidence of acute GVHD (aGVHD).Methods: The current study is a single-institution, retrospective cohort analysis evaluating the effect of tacrolimus metabolism, as studied by CYP3A5 genotype, on incidence of aGVHD. All HCT recipients undergo Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment (PREDICT) testing, which evaluates 184 SNPs within 34 genes relating to the metabolism of five drugs including tacrolimus (via CYP3A5 analysis). Adult pts 18 years and older were included if they received tacrolimus for GVHD prophylaxis after allogeneic HCT and had no evidence of moderate to severe hepatic dysfunction at baseline. Tacrolimus levels were monitored in a uniform manner and doses were adjusted based on levels. Data was collected by manual review of the pts' electronic medical record.Results: Forty-six out of 73 pts screened met the inclusion criteria and were analyzed for the current study. Pts were grouped as either standard responders (39 patients) or hyporesponders (7 patients). Both groups were similar with respect to baseline demographics, disease and transplant-related factors, with the exception of a statistically significant difference in racial composition. There were no African-American pts in the standard responder group and 29% in the hyporesponder group (P =0.003), similar to prior studies [Birdwell K et al, 2012].All pts received an initial tacrolimus dose of 0.045 mg/kg ideal body weight/dose by mouth (PO) twice daily, starting 3 days prior to HCT. Though not statistically significant, pts in the standard responder group achieved a therapeutic tacrolimus dose faster than those in the hyporesponder group (median 14 versus 16 days, P =0.382). The median total daily dose, in PO equivalents, ultimately required for pts who were hyporesponders was 0.125 mg/kg IBW (range 0.063-0.204), which is significantly higher than the median total daily dose required in the standard responder group, 0.070 mg/kg IBW (range 0.014-0.134), (P =0.001).Acute GVHD, only chronic GVHD and no GVHD was seen in 21 (46%), 4 (8%) and 21 (46%) patients, respectively. Thirty-eight of 39 (97%) standard responders and 5 of 7 (71%) hyporesponders survived and maintained their graft to Day +100. Amongst these pts, aGVHD was seen in 18 (47%) pts (grades [gr.] 2-4, 13 patients; gr. 3-4, 2 patients) in the standard group and in 3 (60%) pts (gr. 2-4, 2 patients; gr. 3-4, 2 patients) in the hyporesponder group. Acute GVHD occurred earlier in hyporesponders versus standard responders (median 24 and 27.5 days, respectively) and was more severe. One hundred percent of pts with aGVHD in the standard responder group required systemic steroid therapy, versus 72% of standard responders (P =0.549).Conclusion: Hyporesponders to tacrolimus require increasing doses to achieve similar therapeutic levels compared to standard responders, predisposing them to aGVHD with increased severity. There appears to be a racial disparity in the metabolism of tacrolimus. Additionally, standard responders ultimately required less than our standard initial tacrolimus regimen to achieve a therapeutic level, and may be at excess risk for toxicity when dosed by a standardized regimen. Validation of these findings in a larger, more racially diverse cohort is warranted; results may lead to genotype-driven tacrolimus dosing. DisclosuresNo relevant conflicts of interest to declare.

Effects of CYP3A5 Genotype on Efficacy and Safety of Tacrolimus in Refractory Ulcerative Colitis: An Experience From a Tertiary Referral Center in Japan

Introduction: A calcineurin inhibitor, tacrolimus (TAC), is widely used as an induction therapy for steroid-refractory ulcerative colitis (UC) patients in Japan. Although its efficacy in inducing remission is comparable with other treatment options such as anti-tumor necrosis factor antibodies, its longterm efficacy is not well studied. Its long-term use may lead to an increased incidence of side effects including renal dysfunction. Furthermore, its efficacy as well as toxicity depends on the blood trough level, which requires the frequent monitoring of blood concentration. Both patients and physicians may want to avoid using Tac due to these factors. Here we retrospectively tried to examine the association of genotyping the single nucleotide polymorphism of CYP3A5, the metabolizing enzyme of tacrolimus, with the dosing, long-term efficacy, and incidence of renal dysfunction by TAC for UC in our institution. Methods: Medical records of 21 patients with UC who were treated with TAC for more than 2 weeks were retrospectively reviewed (M:F=13:8). Mean duration of TAC treatment was 308 +/- 284 days. CYP3A5*3(A6986G) was genotyped using the TaqMan real-time polymerase chain reaction assays. 1) Dose of TAC required to reach the therapeutic level (10 ug/ml) 2) incidence of renal dysfunction 3) short- and long-term clinical efficacy outcome was examined in combination of CYP3A5 genotypes. Renal dysfunction was defined by the 25% increase of serum creatinine (Cr). All analyses were conducted under the approval of institutional review board of Kitasato Institute Hospital. Results: CYP3A5*3 genotypes were *3/*3 in 10, *1/*3 in 9, and *1/*1 in 2 patients. 1) The dose required to reach the therapeutic trough level was significantly lower in non-expressor (*3/*3) compared with expressor (*1/*3 and *1/*1). 2) 13 out of 21patients (62%) suffered from renal dysfunction, which was not associated with CYP3A5 genotype but with the trough concentration during the treatment. Most cases recovered after discontinuing or switching Tac to thiopurines. 3) Short- and long-term efficacy outcome was not affected by the genotype. Conclusion: CYP3A5 genotype seemed useful for determining the initial dose of TAC, but was not associated with the incidence of side effects and efficacy. There was a significant proportion of patients who were maintained for longer than 3 months by TAC in combination with thiopurines, however, the incidence of gradual decrease of renal function was frequent.

Gut microbiota and tacrolimus dosing in kidney transplantation.

Tacrolimus dosing to establish therapeutic levels in recipients of organ transplants is a challenging task because of much interpatient and intrapatient variability in drug absorption, metabolism, and disposition. In view of the reported impact of gut microbial species on drug metabolism, we investigated the relationship between the gut microbiota and tacrolimus dosing requirements in this pilot study of adult kidney transplant recipients. Serial fecal specimens were collected during the first month of transplantation from 19 kidney transplant recipients who either required a 50% increase from initial tacrolimus dosing during the first month of transplantation (Dose Escalation Group, n=5) or did not require such an increase (Dose Stable Group, n=14). We characterized bacterial composition in the fecal specimens by deep sequencing of the PCR amplified 16S rRNA V4-V5 region and we investigated the hypothesis that gut microbial composition is associated with tacrolimus dosing requirements. Initial tacrolimus dosing was similar in the Dose Escalation Group and in the Stable Group (4.2±1.1 mg/day vs. 3.8±0.8 mg/day, respectively, P=0.61, two-way between-group ANOVA using contrasts) but became higher in the Dose Escalation Group than in the Dose Stable Group by the end of the first transplantation month (9.6±2.4 mg/day vs. 3.3±1.5 mg/day, respectively, P<0.001). Our systematic characterization of the gut microbial composition identified that fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was 11.8% in the Dose Escalation Group and 0.8% in the Dose Stable Group (P=0.002, Wilcoxon Rank Sum test, P<0.05 after Benjamini-Hochberg correction for multiple hypotheses). Fecal Faecalibacterium prausnitzii abundance in the first week of transplantation was positively correlated with future tacrolimus dosing at 1 month (R=0.57, P=0.01) and had a coefficient±standard error of 1.0±0.6 (P=0.08) after multivariable linear regression. Our novel observations may help further explain inter-individual differences in tacrolimus dosing to achieve therapeutic levels.

Factors associated with optimized tacrolimus dosing in hematopoietic stem cell transplantation

The primary objective was to analyze the initial tacrolimus concentrations achieved in allogeneic hematopoietic stem cell transplantation patients using the institutional dosing strategy of 1 mg IV daily initiated on day +5. The secondary objectives were to ascertain the tacrolimus dose, days of therapy, and dose changes necessary to achieve a therapeutic concentration, and to identify patient-specific factors that influence therapeutic dose. The relationships between the number of pre-therapeutic days and incidence of graft-versus-host disease and graft failure were delineated. A retrospective chart review included adult allogeneic hematopoietic stem cell patients who received tacrolimus for graft-versus-host disease prophylaxis in 2012. Descriptive statistics, linear and logistic regression, and graphical analyses were utilized. Ninety-nine patients met the inclusion criteria. The first concentration was subtherapeutic (<10 ng/ml) in 97 patients (98%). The median number of days of tacrolimus needed to achieve a therapeutic trough was 10 with a median of two dose changes. The median therapeutic dose was 1.6 mg IV daily. Approximately 75% of patients became therapeutic on ≤ 2 mg IV tacrolimus daily. No relationship was found between therapeutic dose and any patient-specific factor tested, including weight. No relationship was found between the number of days of therapy required to achieve a therapeutic trough and incidence of graft-versus-host disease or graft failure. An initial flat tacrolimus dose of 1 mg IV daily is a suboptimal approach to achieve therapeutic levels at this institution. A dose of 1.6 mg or 2 mg IV daily is a reasonable alternative to the current institutional practice.

Role of pharmacogenomics in dialysis and transplantation.

Pharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy. Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant in the kidney transplant field. A potentially clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection being optimized based on CYP3A5 genotype. Although many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes, such as calcineurin inhibitor toxicity and new onset diabetes, is providing new information on patients at risk. Appropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.

Pharmacogenetics of tacrolimus: from bench to bedside?

Tacrolimus (FK-506) is an immunosuppressant widely used to prevent kidney transplant rejection. Patients receive an initial standard dose and tacrolimus levels are measured in blood. If necessary, the dose is adjusted to reach a blood concentration within the accepted range. There is great interindividual variability in the dose required to achieve the target blood level, and many patients require multiple modifications of the dose to reach the range. One of the main determinants of these differences is a CYP3A5 gene polymorphism that determines that about 80% of Caucasians are poor metabolisers and require lower doses compared to the extensive metabolisers. It has been proposed that transplanted patients could receive an initial Tacrolimus dose based on the CYP3A5 genotype. This could reduce the time to achieve the optimal blood level, reducing the number of dose modifications. However, to be accepted by clinicians and translated to the clinical practice this adapted dose procedure should give additional advantages such as a significant reduction of the rates of nephrotoxicity and rejection, or a lower cost due to less dose modifications of Tacrolimus and less antibody induction therapy.

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

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.

Personalized Initial Dose of Tacrolimus Based on CYP3A5 Polymorphism and Its Impact on 1-month Graft Function: A Preliminary Experience

Personalized Initial Dose of Tacrolimus Based on CYP3A5 Polymorphism and Its Impact on 1-month Graft Function: A Preliminary Experience

Personalized Initial Dose of Tacrolimus Based on CYP3A5 Polymorphism and Its Impact on 1-month Graft Function: A Preliminary Experience

Personalized Initial Dose of Tacrolimus Based on CYP3A5 Polymorphism and Its Impact on 1-month Graft Function: A Preliminary Experience

2262 PERSONALIZED INITIAL DOSE OF TACROLIMUS BASED ON THE CYP3A5 POLYMORPHISM AND ITS IMPACT ON THE 1-MONTH GRAFT FUNCTION: A PRELIMINARY EXPERIENCE

INTRODUCTION AND OBJECTIVES: Patients with CYP3A5*1 allele (CYP3A5 expressers) require a higher daily tacrolimus dose than those with CYP3A5*3/*3 genotype (non-expressers) in order to maintain target trough levels (C0) (Tsuchiya, Transplantation, 2004). Recently, we reported that renal cortical interstitial fibrosis (IF) from 0-hour to 1-year post-transplantation increased in non-expressers than CYP3A5 expressers. Unexpected highly tacrolimus levels in non-expressers might influence the development of IF, despite therapeutic drug monitoring (Miura, Transplantation 2011). Therefore, since January 2011, we have started to a personalized initial dosing regimen of controlled-release tacrolimus based on the CYP3A5 polymorphism. The present study investigated the impact of personalized regimen of tacrolimus on the pharmacokinetics and 1-month graft function comparing to the non-personalized regimen. METHODS: Initial oral doses of tacrolimus were 0.20mg/kg for CYP3A5 expressers and 0.10mg/kg for non-expressers. In the nonpersonalized regimen, all patients received 0.20mg/kg of tacrolimus. The target trough levels of tacrolimus were same between the two regimes. RESULTS: Twenty patients were involved in the personalized regimen; CYP3A5 expressers in 6 and non-expressers in 14 cases. Twenty-five patients were in involved in the non-personalized regimen; CYP3A5 expressers in 10 and non-expressers in 15 cases. In the non-personalized regimen, C0 and area under the blood concentrationtime curve (AUC) of tacrolimus and estimated glomerular filtration rate (eGFR) in CYP3A5 expressers and non-expressers were: C0 (4.8 vs. 8.5 ng/ml, p 0.001) and AUC (218 vs. 373 nghr/ml, p 0.001) at day 1 after first administration of tacrolimus, C0 (5.4 vs 7.8 ng/ml, p 0.004) and AUC (218 vs 287 nghr/ml, p 0.013) and eGFR (59.2 vs 42.4 ml/min/1.73m2, p 0.028) at day 28 post-transplantation. In the personalized regimen, C0 and AUC of tacrolimus and eGFR in CYP3A5 expressers and non-expressers were; C0 (6.9 vs 2.7 ng/ml, p 0.279) and AUC (377 vs 136 nghr/ml, p 0.268) at day 1, C0 (8.9 vs 5.2 ng/mL, p 0.0270) and AUC (332 vs 226 nghr/mL, p 0.073) and eGFR (47.7 vs 64.6 ml/min/1.73m2, p 0.202) at day 28. CONCLUSIONS: The personalized medicine of tacrolimus based on the CYP3A5 polymorphism may decrease the pharmacokinetic difference between CYP3A5 expressers and non-expressers, and it may contribute better graft function in non-expressers in the early post-transplantation.

Unusual high dose of tacrolimus in liver transplant patient, a case report

We describe the case of a liver transplant patient who had great difficulty in reaching the desired trough blood levels despite the use of high dose tacrolimus. The patient was homozygous for the CYP3A5*3 allele. However, the respective donor carried the wild-type CYP3A5*1/*1 genotype. Regarding ABCB1 SNPs at exon 21 and 26, the patient showed the 2677GT and 3435CC genotypes. For the corresponding donor we observed the 2677GG and 3435CC wild-type genotypes. One, two and three weeks after transplantation the patient received daily 0.219, 0.287 and 0.273 mg/kg of tacrolimus, respectively. However, the corresponding tacrolimus trough blood levels were of 4.6, 5.6 and 6.1 ng/mL. The tacrolimus target level of 10.4 ng/mL was finally reached after 1 month of therapy. During the entire period of observation the kidney showed no sign of damage. No other signs of toxicity were reported except for the occurrence of an isolated systolic hypertension. CYP3A5 genotyping may represent a useful tool to better evaluate the appropriate initial dose of tacrolimus for patients carrying a liver with the CYP3A5*1/*1 genotype.