Tacrolimus Dose Requirements Research Articles

Using tacrolimus in living donor liver transplantation recipients with high model for end-stage liver disease scores might increase the risk of postoperative neuropsychologic deficits

For decompensated liver cirrhosis and hepatocellular carcinoma, liver transplantation provides these patients the only curative treatment option with better long-term results. The Model for End-stage Liver Disease (MELD) system is a good tool to predict short-term mortality among these patients and has also been applied to allocate liver grafts to patients on waiting lists in several countries.1 In 2002, the New York State Committee on Quality Improvement in Living Liver Donation prohibited live liver donation for potential recipients with MELD scores greater than 25.2 Alves et al suggested MELD scores >18 was associated with higher probability of graft failure after living donor liver transplantation (LDLT).3 Previous studies have demonstrated that using tacrolimus as primary immunosuppressant, neuropsychologic deficits had been found to be higher in recipients with elevated preoperative MELD scores, especially for those MELD scores greater than 15.4,5 We here summarize our experiences on postoperative neuropsychologic deficits in LDLT recipients using tacrolimus with high MELD scores. From 2004 to 2012, 218 LDLT were performed in our transplant center. Postoperative neuropsychologic deficits were observed in 8 male recipients (3.7%) during the first week, including: insomnia (2), vivid dreams (1), paresthesias (1), anxiety (1), agitation (2), and cognitive impairment (1). The mean age was 42 (33-57) and the mean MELD score was 21 (9-28). All of the patients did not have the history of excessive alcohol use and preexisting central nervous system damage. Decompensated liver cirrhosis caused by HBV infection was seen in 5 patients, while hepatocellular carcinoma (HCC) was seen in 3 patients. Right living lobe liver transplantations were performed by the same medical team, with a mean graft to body weight ratio (GBWR) 0.78 (0.6-1.0). Our center used tacrolimus as the initial immunosuppressant for all liver transplant recipients. In the first postoperative week, the mean tacrolimus blood level was 9.3 (6.511.6), while the mean total bilirubin blood level was 23mmol/L (15-30mmol/L), the mean creatinine blood level was 67umol/L (45-90umol/L), and the mean serum sodium level was 139mmol/L (136-143mmol/L). The mean ICU stays was 9 days (7-12 days). After switching tacrolimus to sirolimus, all recipients were relieved from neuropsychlologic deficits and discharged eventually without primary graft non-function, renal failure, acute rejection, re transplantation or death. All the 8 recipients had a relatively higher MELD scores to other LDLT recipients. Although the mechanistic pathway resulting in these neural deficits is not clear, our hypothesis is that several reasons might contribute to it: 1) elevated preoperative MELD scores usually represents a poor liver function, potential encephalopathy risk, and increased susceptibility to blood-brain barrier disruption, associating with increased vulnerability to postoperative tacrolimus neurotoxicity; 2) when GBWR <0.8, a small-for-size (SFS) living graft recipients have significantly decreased tacrolimus dosage requirements compared with non-SFS grafts recipients in LDLT. A regular dosage may cause higher tacrolimus blood levels in these SFS graft recipients and elevated blood levels of tacrolimus are associated with neurotoxicity6; 3) in order to ensure the donor safety, a SFS graft may be transplanted to a high MELD recipient. This interaction may apparently increase the postoperative neuropsychologic deficits risk in such group of patients. Although the switching from tacrolimus to sirolimus can effectively relieve patients’ neuropsychlologic deficits, there are potential risks in graft primary non-function, infection, and 1. Hongyu Li, 2. Bo Li, PhD, MD, 3. Yonggang Wei, MD, 1-3: Department of Liver and Vascular Surgery, Center of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.

CYP3A5 Genotype Had no Impact on Intrapatient Variability of Tacrolimus Clearance in Renal Transplant Recipients

The risk of long-term chronic allograft nephropathy and graft loss after kidney transplantation is increased in patients with a high intrapatient variability in the clearance of tacrolimus. CYP3A5 genotype has a significant influence on the oral bioavailability of tacrolimus and is a potential influence on variability of exposure. The study population consisted of 118 renal transplant recipients with stable renal function 12 months after transplant. The intrapatient variability of tacrolimus concentration was calculated. The patients were divided into low- and high-intraindividual variability groups using the median variability of tacrolimus clearance as the cutoff value. No differences in baseline characteristics were observed between the expressers (n = 37) and nonexpressers (n = 81) except for ethnicity, which is in line with previous observations. Tacrolimus dose requirement was significantly higher in patients expressing CYP3A5, confirming earlier observations (P < 0.0001). However, intraindividual variability of tacrolimus clearance was not related to CYP3A5 genotype (P = 0.3331). The intrapatient variability of tacrolimus clearance was not associated with CYP3A5 genotype in stable renal transplant recipients.

Response to “CYP3A5 Genotype, but Not CYP3A4*1b, CYP3A4*22, or Hematocrit, Predicts Tacrolimus Dose Requirements in Brazilian Renal Transplant Patients”

Response to “CYP3A5 Genotype, but Not CYP3A4*1b, CYP3A4*22, or Hematocrit, Predicts Tacrolimus Dose Requirements in Brazilian Renal Transplant Patients”

Effect of MDR1 Polymorphisms on the Blood Concentrations of Tacrolimus in Turkish Renal Transplant Patients

BackgroundTacrolimus, a calcineurin inhibitör, is prescribed to prevent allograft rejection in renal transplantation. Tacrolimus not only has a narrow therapeutic index, but also shows significant interindividual differences. The absorption and metabolism of this drug are affected by multidrug resistance (MDR) 1 gene polymorphisms that correlated with single-nucleotide polymorphisms (SNPs) affecting in vivo P-glycoprotein activity. This study investigated associations of MDR1 gene C3435T polymorphism with tacrolimus blood concentrations and dose requirements as well as acute rejection episodes among Turkish renal transplant patients. MethodsOne hundred living-donor transplant recipients and 150 healthy control subjects underwent C3435T genotyping using polymerase chain reaction–restriction fragment length polymorphism. Blood concentrations of tacrolimus were determined with the cloned enzyme donor immunoassay. ResultsThe CC, CT, and TT genotype frequencies among patients were, respectively, 44.0%, 33.0%, and 23.0% versus 36.7%, 43.3%, and 20.0% among control subjects. There was no significant difference between (P = .061; P = .102; P = .211; respectively). The ratio of blood concentration to dose of tacrolimus for patients with mutant homozygous 3435 TT genotype was higher than that of wild-type 3435 CC genotype homozygous individuals. The doses for these patients were lower at 1, 3, and 12 months (P = .048; P = .03; P = .041, respectively). There were no significant differences between the groups regarding coprescription of drugs that affect tacrolimus concentrations, such as diltiazem. Acute rejection episodes were not associated with the CC vs CT or TT genotypes: odds ratio (OR), 0.517 (95% confidence interval [CI], 0.190–1.407; P = .192); OR 1.558 (95% CI, 0.587–4.136; P = .372); OR 1.346; (95% CI, 0.456–3.968; P = .590), respectively. ConclusionsDetermination of MDR1 polymorphism may help to achieve target of tacrolimus blood concentrations.

The impact of CYP3A5 and MDR1 polymorphisms on tacrolimus dosage requirements and trough concentrations in pediatric renal transplant recipients

Previous international studies demonstrated significant heterogeneity in the tacrolimus (TAC) dose required to attain target blood concentrations, attributed to both genetic and ethnic factors. While the majority of previous reports on adult recipients of renal, heart and liver transplants have shown a significant effect of CYP3A5FNx013 single nucleotide polymorphisms (SNPs) on TAC pharmacokinetics (PKs), the impact of multidrug resistance protein 1 (MDR1) and SNPs remains controversial. Yet, similar data of TAC in pediatric populations, in whom the intra- and inter-subject variations are likely to be even greater, is currently limited. We aimed to examine the influence of various CYP3A5 and MDR1 genotypes on TAC dose requirements and PKs in the Jordanian pediatric renal transplant population. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013 and MDR1 C3435T. Dose-adjusted trough concentrations (C 0 /D) and daily doses (D) were compared among different CYP3A5 and MDR1 genotypes in the early and maintenance phases post-transplant. Surprisingly, there were no significant differences in D, C 0 or C 0 /D among the genotypes of CYP3A5 or MDR1 polymorphisms in either the early or the maintenance phase after transplantation, whereas after combining the C 0 /D levels of MDR1 C allele expressers, noticeably lower TAC levels were observed as compared with the TT genotype. However, the difference became not significant beyond 3 months. Based on a pharmacogenetic evaluation, the independent impact of CYP3A5 SNPs on TAC PKs was not evident, demonstrating the need for further large-scale studies.

Response to “Pretransplantation Pharmacokinetic Assessments to Predict Posttransplantation Dosing Requirements in Renal Transplant Recipients: What Is Known?”

To the Editor: We appreciate the opportunity to respond to “Pretransplantation Pharmacokinetic Assessments to Predict Posttransplantation Dosing Requirements in Renal Transplant Recipients: What Is Known?,” by van Maarseveen and van Zuilen.1 On the basis of published data that show a poor correlation between pre- and posttransplantation tacrolimus pharmacokinetics, the authors doubt that pretransplantation assessment of in vivo CYP3A4 activity might be a promising strategy to predict posttransplantation tacrolimus dose requirements.

African American (AA) Renal Transplant Recipients (RTR) Require Higher Tacrolimus Doses to Achieve Target Levels Compared to White RTR: Does Clotrimazole (CTZ) Help?

The number of African Americans on the kidney waiting list is increasing in the USA. Several studies showed that AAs are at higher risk for rejection and graft loss. Due to genetic polymorphisms, AA may metabolize CNI faster than White individuals. The goal of this study is to evaluate the tacrolimus dose required to reach therapeutic levels and to assess the impact of CTZ on tacrolimus metabolism in AA compared to White patients. One hundred forty-two AA renal transplant recipients (RTR) were compared to 312 White RTR. Demographics were similar in both groups (Table 1). Induction therapy and maintenance immunosuppression were similar in both groups and included tacrolimus, mycophenolate acid (MPA) and steroids. The goal in all RTR was to maintain a 12 hour trough level of 10-15 ng/ml in the first 3 months, 8-10 ng/ml for the first year and 5-8 ng/ml thereafter. To achieve these levels, AA require a significantly higher dosage of tacrolimus compared to Whites (5.9±2.9 vs. 3.6±2 mg/d respectively, p< 0.0001). By multivariate analysis, tacrolimus dose requirements were not affected by age, gender, MPA or prednisone dose, diabetes and renal function. Both male and female AA required a higher dose of tacrolimus compared to White male and female respectively. Adding CTZ to the RTR regimen significantly reduced the tacrolimus dose requirements in all RTR. When CTZ was used, the tacrolimus dose requirement was not statistically significant between AA and Whites (2.6±1.2 mg/d vs. 1.8±1.5 mg/d, p=0.07).Table: [*=p<0.05]We conclude that AA required a higher tacrolimus dose to reach the desired trough level in RTR compared to White RTR. The use of CTZ significantly reduces the tacrolimus dose and eliminates the need for higher doses of tacrolimus in AA RTR. Thus, for AA who would require a high dose of tacrolimus, use of CTZ may benefit these RTR in order to avoid both the higher dose and cost of tacrolimus.

In Vivo CYP3A4-Activity, CYP3A5-Genotype and Hematocrit Predict Tacrolimus Dose-Requirements and Clearance in Renal Transplant Recipients

Introduction: Tacrolimus (Tac) is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and a high interindividual variability in pharmacokinetics. It has been hypothesized that the latter is due to interindividual differences in in vivo CYP3A4-activity and genetically determined CYP3A5 expression (CYP3A5*1 SNP). Methods: Cross-sectional study in 59 renal transplant recipients tested 3 months after transplantation investigating the relationship between in vivo CYP3A4-activity (assessed using midazolam (MDZ) as a drug probe) and CYP3A5 genotype (CYP3A5*1-allele carriers vs. CYP3A5*3/*3 homozygous patients), and Tac pharmacokinetics (assessed using dose interval concentration time profiles), taking into account other possible determinants of Tac disposition. Of note, systemic MDZ clearance (MDZ Cl) reflects hepatic CYP3A4-activity, whereas apparent oral MDZ clearance (MDZ Cl/F) reflects in vivo CYP3A4 mediated first pass metabolism and thus combined intestinal and hepatic CYP3A4-activity. Results: Baseline characteristics did not differ between CYP3A5 expressers (CYP3A5*1-allele carriers, n=10) and non-expresser (CYP3A5*3/*3 homozygous patients, n=49). Tac dose requirements (D), dose corrected AUC (AUC0-12/D) and clearance (Clss) were respectively 1.8-fold higher, 2-fold lower and 1.8-fold higher in CYP3A5 expressers. MDZ Cl and MDZ Cl/F did not differ between genotype groups. Figures 1 and 2 depict the relationship between MDZ Cl/F and Tac D (Fig 1) and Tac Clss (Fig 2) in CYP3A5 expressers (red dots) and non-expressers (blue dots), as well as the bivariate (MDZ Cl/F and CYP3A5 genotype) models predicting Tac D and Tac Clss respectively. In multivariate regression analysis MDZ Cl/F, CYP3A5 genotype and hematocrit independently predicted Tac D, Tac AUC0-12/D and Tac Clss: model R2 0.60-0.70, partial R2CYP3A5 genotype 0.31-0.33, partial R2 MDZ Cl/F 0.25-0.26 and partial R2 hematocrit 0.04-0.11 (p< 0.0001 for all).[Fig 1][Fig 2]Conclusion: In renal transplant recipients in vivo CYP3A4-activity (reflected by apparent oral midazolam clearance) and CYP3A5 genotype explain 55-60 % of interindividual variability in tacrolimus dose-requirements and clearance, while hematocrit accounts for an additional 10 %. These results demonstrate the importance of CYP3A mediated tacrolimus metabolism for explaining the clinically observed high interindividual variability in tacrolimus pharmacokinetics and provide a potential basis for a comprehensive approach in predicting tacrolimus dose requirements in individual patients.

Tacrolimus Dose Requirements in the First Week and the Development of the Early Postoperative Complications in Pediatric Living Donor Liver Transplant Recipients

Tacrolimus Dose Requirements in the First Week and the Development of the Early Postoperative Complications in Pediatric Living Donor Liver Transplant Recipients

Pretransplantation Pharmacokinetic Assessments to Predict Posttransplantation Dosing Requirements in renal Transplant Recipients: What Is Known?

To the Editor: We appreciate the opportunity to respond to “Pretransplantation Pharmacokinetic Assessments to Predict Posttransplantation Dosing Requirements in Renal Transplant Recipients: What Is Known?,” by van Maarseveen and van Zuilen.1 On the basis of published data that show a poor correlation between pre- and posttransplantation tacrolimus pharmacokinetics, the authors doubt that pretransplantation assessment of in vivo CYP3A4 activity might be a promising strategy to predict posttransplantation tacrolimus dose requirements.

In Vivo CYP3A4 Activity, CYP3A5 Genotype, and Hematocrit Predict Tacrolimus Dose Requirements and Clearance in Renal Transplant Patients

Tacrolimus is metabolized by CYP3A4 and CYP3A5 and is characterized by a narrow therapeutic index and highly variable pharmacokinetics. This cross-sectional study in 59 renal transplant patients investigated the relationship among in vivo CYP3A4 activity (assessed using midazolam as a drug probe), CYP3A5 genotype on the one hand, and tacrolimus pharmacokinetics on the other hand, taking into account other potential determinants of tacrolimus disposition. In vivo CYP3A4 activity and CYP3A5 genotype explain 56-59% of variability in tacrolimus dose requirements and clearance, contributing ~25 and 30%, respectively. Hematocrit explains an additional 4-14%. These data indicate that CYP3A4- and CYP3A5-mediated tacrolimus metabolisms are major determinants of tacrolimus disposition in vivo and explain a substantial part of the clinically observed high interindividual variability in tacrolimus pharmacokinetics. Furthermore, these data provide a potential basis for a comprehensive approach to predicting tacrolimus dose requirement in individual patients and hence provide a strategy to tailor immunosuppressive therapy in transplant recipients.

CYP3A5 Polymorphism in Mexican Renal Transplant Recipients and its Association with Tacrolimus Dosing

Variability in CYP3A5 expression associated with differences in tacrolimus bioavailability has been documented. The wild-type allele CYP3A5*1 expresses the functional protein, whereas the CYP3A5*3 allele is a splice variant with a premature stop codon and encodes a truncated nonfunctional protein. The aim of the study was to determine the frequency of CYP3A5*1 and CYP3A5*3 in 291 (124 adults, 167 pediatric) Mexican renal transplant recipients, evaluate the tacrolimus dose requirements by genotype and compare genotype frequency data with that of other populations. We carried out a multicenter study. Patients were recruited from three institutions located in Mexico City. Genotyping of the CYP3A5*1 and CYP3A5*3 alleles was performed by direct DNA sequencing. Eighteen patients (6.2%) were CYP3A5*1*1 homozygous carriers or functional protein expresser homozygous, 121 patients (41.6 %) were CYP3A5*1*3 were heterozygous carriers or heterozygous expressers, and 152 patients (52.2%) were CYP3A5*3*3 homozygous carriers or homozygous nonexpressers. There was a statistically significant difference in frequency of the functional and nonfunctional expresser phenotypes from those reported for Black and Caucasian, but not for South Asian populations. The CYP3A5 phenotype had a significant impact in tacrolimus bioavailability, as wild-type carriers required higher dosing compared to mutated carriers to achieve similar drug trough levels. Patients with CYP3A5*1*1 genotype had a median dose requirement of 0.16 mg/kg/day, CYP3A5*1*3 patients had a median tacrolimus dose of 0.13 mg/kg/day and CYP3A5*3*3 had a median dose of 0.07 mg/kg/day (Kruskal-Wallis, p <0.0001). Of the Mexican transplant recipients, 52.2% were CYP3A5*3*3 and required significantly lower tacrolimus dose than those with CYP3A5*1 allele.

Identification of Factors Affecting Tacrolimus Level and 5‐Year Clinical Outcome in Kidney Transplant Patients

The purpose of this study was to identify and characterize the association of various clinical variables and CYP3A5 genotypes with the pharmacokinetics of tacrolimus and outcome over 1-5 years in kidney transplantation patients in Korea. A total of 129 recipients (aged 18-65 years) administered tacrolimus were genotyped for CYP3A5 (6986A>G in intron 3; rs776746). Clinical covariates and trough levels, doses and dose-adjusted trough levels of tacrolimus, as well as complications during the 1-5 years after transplantation, were analysed. A linear mixed model was used to investigate potential factors affecting the trough levels, doses and dose-adjusted levels of tacrolimus. We identified factors affecting chronic allograft nephropathy (CAN) and tacrolimus-related complications. After adjusting for sex, body-weight and doses of corticosteroids and mycophenolate mofetil, we noted that CYP3A5 genotypes had the most profound effect on the dose and dose-adjusted trough levels of tacrolimus 1-5 years after transplantation (p < 0.001). Trough levels of tacrolimus were associated with post-transplantation hyperlipidaemia (p < 0.05), and estimated glomerular filtration rate was associated with CAN (p < 0.05). Therefore, the CYP3A5 genotype is a variable marker for tacrolimus dose requirement, and the trough level of tacrolimus should be controlled to minimize post-transplant hyperlipidaemia to achieve optimum outcome.

Association Between Tacrolimus Concentration and Genetic Polymorphisms of CYP3A5 and ABCB1 During the Early Stage After Liver Transplant in an Iranian Population

Tacrolimus is widely used as an immunosuppressive drug in liver transplant recipients with a narrow therapeutic range and variable individualized pharmacokinetics. Tacrolimus is a substrate of cytochrome P-450 3A enzyme and the drug transporter, P-glycoprotein. We determined the genotypic frequencies of cytochrome P-4503A5 (rs776746), and ABCB1 (rs1045642), single nucleotide polymorphisms in a population of 100 Iranian liver transplant patients, and investigated the influence of the above-mentioned single nucleotide polymorphisms on tacrolimus concentrations. At 7 and 30 days after transplant, tacrolimus dosages (mg/kg/d), trough blood levels (T0), and dose-adjusted concentrations (concentration/dosage ratio) were determined. Polymerase chain reaction, followed by restriction fragment length polymorphism analysis, was used for genotyping cytochrome P-4503A5*3 [6986A>G] as well as ABCB1 [3435C>T]. Ninety-five percent of the population showed a cytochrome P-4503A5*3/*3 genotype. ABCB13435TT genotype was observed in 33 cases (33%); whereas 51 cases (51%) carried 3435CT, and 16 cases (16%) carried 3435CC. With regard to the ABCB1 and cytochrome P-4503A5, they showed no influence on tacrolimus dosing requirements at 1 week or 1 month after transplant. No association of any genetic variant with the acute rejection rate was found. Finally, as the liver donor genotype influences tacrolimus pharmacokinetics with regard to expression of cytochrome P-4503A5, far more than the genotype of the recipient; therefore, it should be considered before recommending any personal immunosuppressive treatment based on pharmacogenetics.

The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients

Tacrolimus, an immunosuppressive drug widely prescribed in kidney transplantation, requires therapeutic drug monitoring due to its marked interindividual pharmacokinetic variability and narrow therapeutic index. Previous studies have established that CYP3A5 rs776746 is associated with tacrolimus clearance, blood concentration, and dose requirement. The importance of other drug absorption, distribution, metabolism, and elimination (ADME) gene variants has not been well characterized. We used novel DNA biobank and electronic medical record resources to identify ADME variants associated with tacrolimus dose requirement. Broad ADME genotyping was performed on 446 kidney transplant recipients, who had been dosed to a steady state with tacrolimus. The cohort was obtained from Vanderbilt's DNA biobank, BioVU, which contains linked deidentified electronic medical record data. Genotyping included Affymetrix drug-metabolizing enzymes and transporters Plus (1936 polymorphisms), custom Sequenom Massarray iPLEX Gold assay (95 polymorphisms), and ancestry-informative markers. The primary outcome was tacrolimus dose requirement defined as blood concentration to dose ratio. In analyses, which adjusted for race and other clinical factors, we replicated the association of tacrolimus blood concentration to dose ratio with CYP3A5 rs776746 (P=7.15×10), and identified associations with nine variants in linkage disequilibrium with rs776746, including eight CYP3A4 variants. No NR1I2 variants were significantly associated. Age, weight, and hemoglobin were also significantly associated with the outcome. In final models, rs776746 explained 39% of variability in dose requirement and 46% was explained by the model containing clinical covariates. This study highlights the utility of DNA biobanks and electronic medical records for tacrolimus pharmacogenomic research.

The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation

The aim of this study was to evaluate the effect of different clinical covariates on tacrolimus dose requirements in adult kidney transplant patients with a specific focus on drug interactions. Tacrolimus dosing requirement, normalized by drug levels and expressed as the concentration/dose (C/D) ratio as a surrogate index of tacrolimus bioavailability, was employed to identify four categories of tacrolimus dosing requirement, namely, very high, high, small, and very-small, in very fast, fast, slow, and very slow metabolizers, respectively. Steroid weight-based doses were analyzed instead of fixed doses, and genetic analysis of cytochrome P450 (CYP) 3A5*1/*3 and multi-drug resistance 1 (MDR1) C3435T and C1236T polymorphisms were performed Multivariate analysis on 450 adult transplant patients identified six risk factors for being slow metabolizers and therefore requiring small tacrolimus doses: male sex (OR 1.615, p = 0.020); age >60 years (OR 2.456, p = 0.0005); body mass index ≥ 25 (OR 1.546, p = 0.046), hepatitis C virus positivity (OR 2.800, p = 0.0004); low steroid dose <0.06 mg/kg (OR 3.101, p < 0.0001). Patients with a small tacrolimus requirement were at increased risk for multiple infections (OR 1.533, p = 0.0008) and higher systolic blood pressure (OR 1.385, p = 0.022) and showed a significant association with the CYP3A5*3/*3 genotype adjusted by MDR1 polymorphisms C3435T and C1236T (OR 8.104, p = 0.0001). Our results demonstrate the importance of the interaction among genetic and clinical factors in conditioning tacrolimus disposition, with corticosteroid weight-based dose being the only modifiable risk factor for tacrolimus requirement. As the tacrolimus dosing requirement increases with increasing tacrolimus clearance through concomitant steroid use, undesirable changes in tacrolimus levels may occur when steroid doses are tapered, predominantly in slow metabolizers. This often neglected drug interaction has to be monitored to optimize tacrolimus exposure in kidney transplant patients.

Association of MDR1 Gene SNPs and Haplotypes with the Tacrolimus Dose Requirements in Han Chinese Liver Transplant Recipients

BackgroundThis work seeks to evaluate the association between the C/D ratios (plasma concentration of tacrolimus divided by daily dose of tacrolimus per body weight) of tacrolimus and the haplotypes of MDR1 gene combined by C1236T (rs1128503), G2677A/T (rs2032582) and C3435T (rs1045642), and to further determine the functional significance of haplotypes in the clinical pharmacokinetics of oral tacrolimus in Han Chinese liver transplant recipients.Methodology/Principal FindingsThe tacrolimus blood concentrations were continuously recorded for one month after initial administration, and the peripheral blood DNA from a total of 62 liver transplant recipients was extracted. Genotyping of C1236T, G2677A/T and C3435T was performed, and SNP frequency, Hardy-Weinberg equilibrium, linkage disequilibrium, haplotypes analysis and multiple testing were achieved by software PLINK. C/D ratios of different SNP groups or haplotype groups were compared, with a p value<0.05 considered statistically significant. Linkage studies revealed that C1236T, G2677A/T and C3435T are genetically associated with each other. Patients carrying T-T haplotype combined by C1236T and G2677A/T, and an additional T/T homozygote at either position would require higher dose of tacrolimus. Tacrolimus C/D ratios of liver transplant recipients varied significantly among different haplotype groups of MDR1 gene.ConclusionsOur studies suggest that the genetic polymorphism could be used as a valuable molecular marker for the prediction of tacrolimus C/D ratios of liver transplant recipients.

Lower tacrolimus daily dose requirements and acute rejection rates in the CYP3A5 nonexpressers than expressers

CYP3A5 genetic polymorphisms contribute to marked interindividual differences in the metabolism of and response to tacrolimus in humans. This study was aimed to clarify the impact of the CYP3A5*3 variant on tacrolimus dose requirements and acute rejection rates in patients with organ transplantation. A literature search was performed up to August 2009 by using the Cochrane library, PubMed, Medline, and EMBase. Twenty-three studies (a total of 1779 patients) were included in this meta-analysis. Eighteen studies (1443 patients) were involved in renal transplantation and five studies (336 patients) in liver transplantation. Results of meta-analysis demonstrated that, in renal transplant patients, despite the presence of significant heterogeneity, CYP3A5 expressers required higher mean tacrolimus daily doses by 0.045 mg/kg (95% confidence interval (CI), 0.033-0.056) than nonexpressers. Furthermore, sub-analysis of the time of posttransplantation showed that CYP3A5 expressers required higher daily doses than nonexpressers by 0.010, 0.084, 0.041, 0.037, and 0.044 mg/kg at week 2, and at month 1, 3, 6, and 12, respectively. Subset analysis of the ethnicity of organ recipients indicated that mean tacrolimus daily doses were 0.056, 0.037, and 0.077 mg/kg higher in CYP3A5 expressers than non- expressers for white, Chinese, and Japanese patients, respectively. In contrast, for liver transplant patients, higher tacrolimus daily doses were required not only in CYP3A5 expressers of the organ donors than nonexpressers by 0.024 mg/kg (95% CI, 0.019-0.028), but also in CYP3A5 expresser of the organ recipients than nonexpresser by 0.012 mg/kg (95% CI, 0.005-0.018). However, a significant difference in the acute organ rejection rate was observed only at one month (odds ratio, 3.27; 95% CI, 1.57-6.81; P=0.002). Tacrolimus daily dose requirements may vary with the presence of the CYP3A5*3 variant, ethnicity of the organ recipients, and the time of posttransplantation. In addition, the acute organ rejection rate may be higher in CYP3A5 expressers than nonexpressers over the first month after transplantation.

Age and CYP3A5 genotype affect tacrolimus dosing requirements after transplant in pediatric heart recipients

Tacrolimus is one of the commonly used immunosuppressive drugs for pediatric heart transplants. Large variation exists in pharmacokinetics during the direct post-transplant period, resulting in an increased risk of adverse events. Limited data are available on the interaction of age, CYP3A5 and ABCB1 genotype, and disease severity on the variation in disposition and outcome in pediatric heart transplant recipients. We studied the relationship between age and CYP3A5 and ABCB1 genotype and the Pediatric Risk of Mortality (PRISM) score on tacrolimus dose (mg/kg), steady-state trough concentrations, and concentration/dose ratio, as well as rejection and renal function for 14 days after heart transplant in children. Tacrolimus was administered to 39 children (median age, 6.0 years) after transplant. A correlation was found between the age at the time of transplant and the tacrolimus dosing requirements (r(s) = -0.447, p = 0.004) and the concentration/dose ratio (r(s) = 0.351, p = 0.029). CYP3A5 expressors required median (interquartile range) higher doses of tacrolimus (0.14 [0.09] vs 0.06 [0.04] mg/kg/12 hours, p = 0.001), and had lower concentration/dose ratios (45.34 [44.54] vs 177.78 [145.38] ng/ml per mg/kg/12 hours, p < 0.0001). This relationship was not seen with the ABCB1 genotype. Age and CYP3A5 genotype predicted the tacrolimus dosing requirements as well as the concentration/dose ratio (R(2) = 0.351, p = 0.001 and R(2) = 0.521, p < 0.001). No relationship was found between any of the CYP3A5 or ABCB1 genotypes and the estimated glomerular filtration rate. Younger age and CYP3A5 expressor genotype were independently associated with higher dosing requirements and lower tacrolimus concentration/dose ratios.

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients

Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.