Tacrolimus Disposition Research Articles

Personalized tacrolimus dose requirement by CYP3A5 but not ABCB1 or ACE genotyping in both recipient and donor after pediatric liver transplantation.

Tacrolimus (TAC) is the backbone of an immunosuppressive drug used in most solid organ transplant recipients. A single nucleotide polymorphism (SNP) at position 6986G>A in CYP3A5 has been notably involved in the pharmacokinetic variability of TAC. It is hypothesized that CYP3A5 genotyping in patients may provide a guideline for TAC therapeutic regimen. To further evaluate the impact of CYP3A5 variants in donors and recipients, ABCB1 and ACE SNPs in recipients on TAC disposition, clinical and laboratory data were retrospectively reviewed from 90 pediatric patients with liver transplantation and their corresponding donors after 1 year of transplantation. The recipients with CYP3A5 *1/*1 or *1/*3 required more time to achieve TAC therapeutic range during the induction phase, and needed more upward dose during the late induction and the maintained phases, with lower C/D ratio, compared with those with CYP3A5 *3/*3. And donor CYP3A5 genotypes were found to impact on TAC trough concentrations after liver transplantation. No association between ABCB1 or ACE genotypes and TAC disposition post-transplantation was found. These results strongly suggest that CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized TAC dosage regimen in pediatric liver transplant patients.

Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients

Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients. Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Co : dose). We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co : dose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5-175.4) vs. 71.3 (45.6-109.0), P < 0.0001 and 151.8 (112.1-205.6) vs. 109.6 (58.1-132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co : dose ratio compared with non-TTT/TTT individuals [167.8 (130.4-218.0) vs. 119.4 (100.2-166.3), P = 0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors. CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration.

(301) - Effect of CYP3A4*22 and CYP3A5 Combined Genotypes on Tacrolimus Disposition in Heart Transplantation

The CYP3A4*22 and CYP3A5*3 polymorphisms have been associated with decreased tacrolimus (TAC) metabolism and decreased TAC dose requirements in numerous transplant (Tx) populations. The objective of this study was to determine the combined impact of CYP3A4*22 and CYP3A5*3 genotypes on TAC disposition in heart transplant (HTx) recipients.

Population Pharmacokinetics of Tacrolimus in Adult Kidney Transplant Patients

The aims of this study were to develop a population pharmacokinetic model of tacrolimus in adult kidney transplant recipients, to use this model to compare cytochrome P450 3A5 (CYP3A5) genotype-based initial dosing of tacrolimus with standard per-kilogram-based dosing, and to predict the best starting dose of tacrolimus based on patient genotype to achieve a trough concentration between 6 and 10 µg/L by day 5 posttransplantation. Population analysis was performed using the software program NONMEM. Tacrolimus dosing regimens were compared by predicting tacrolimus trough concentrations in a simulated data set by running NONMEM with population parameters fixed at the final model estimates. Data from 173 patients with 1554 tacrolimus concentration-time measurements were modeled. Tacrolimus disposition was well described by a 2-compartment model with first-order elimination and first-order absorption after a lag time. Patient CYP3A5 genotype (rs776746), weight, hematocrit, and postoperative day were identified as significant covariates effecting tacrolimus apparent oral clearance (CL/F), with higher CL/F in CYP3A5*1 allele carriers, heavier patients, patients with low hematocrit, and in the immediate posttransplantation period. Typical population estimates for tacrolimus CL/F in CYP3A5*1 allele carriers and noncarriers were 40.8 and 25.5 L/h, respectively. In patients carrying the CYP3A5*1 allele, a per-kilogram dose of 0.075 mg/kg twice daily seemed too much low with approximately 65% of simulated subjects predicted to achieve a trough below 6 µg/L at day 5 posttransplantation. To reduce the risk of under immunosuppression in the immediate posttransplantation period, carriers of a CYP3A5*1 allele are likely to benefit from a tacrolimus starting dose of either 10 mg or 0.115 mg/kg twice daily.

P450 Oxidoreductase *28 (POR*28) and Tacrolimus Disposition in Pediatric Kidney Transplant Recipients—A Pilot Study

Both age and CYP3A5 genotype are important determinants of tacrolimus disposition in pediatric kidney transplant recipients. In a recent study in adults, POR*28 was associated with increased dosing requirements early after transplant of CYP3A5-expressing kidney transplant recipients. The authors aimed to evaluate the additional contribution of POR*28 to early tacrolimus disposition in pediatric kidney transplant recipients. Retrospective data of 43 pediatric kidney transplant recipients up to 14 days posttransplant were evaluated on tacrolimus dose and tacrolimus predose blood concentrations. Recipient POR*28 and CYP3A5 genotype were determined. CYP3A5 expressers carrying at least 1 POR*28 allele had on average 18.3% lower tacrolimus predose concentrations and 20.2% lower concentration/dose ratios compared with CYP3A5 expressers with POR*1/*1 genotype (P = 0.002 and P = 0.001, respectively). In CYP3A5 nonexpressers, tacrolimus disposition did not significantly differ between POR genotypes. In this small cohort of pediatric kidney transplant recipients, POR*28 genotype seems to explain part of the variability found in tacrolimus disposition, in addition to age and CYP3A5 genotype. This finding should be validated in a larger population, and it would be worthwhile to evaluate the clinical impact of this genotype.

PP132—Contribution of genetic (CYP3A5, ABCB1 and POR) and non-genetic variables to the oral tacrolimus clearance in children’s with stable kidney transplant, during advagraf® treatment

There is a large interindividual variation in tacrolimus (TAC) disposition. Genetic information (mainly CYP3A5) has been shown to influence TAC pharmacokinetics and potentially contribute to the optimization of its dosing. The aim of this study was to evaluate the influence of genetic and clinical factors on TAC pharmacokinetic variability in stable pediatric renal transplant patients.

CYP3A4*22 and CYP3A Combined Genotypes Both Correlate With Tacrolimus Disposition in Pediatric Heart Transplant Recipients

Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients. Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers. CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001). Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.

Pharmacokinetic interaction between tacrolimus and berberine in a child with idiopathic nephrotic syndrome

Berberine is a major isoquinoline alkaloid in herbs such as goldenseal, berberis, and Coptis chinensis and has been traditionally used to treat diarrhea [1]. We report here a welldocumented interaction between tacrolimus and berberine in a child with idiopathic nephrotic syndrome. A 16-year-old child was confirmed to have nephrotic syndrome after observation of 1-month history of generalized edema associated with persistent proteinuria in April 2012. The immunosuppressive therapy was initialed with prednisone (60 mg/m/day), frequent relapses occurs when prednisone dose was reduced to 40 mg/m/day. Tacrolimus (0.1 mg/kg, twice daily) was then added to immunosuppressive therapy. Tacrolimus dosage adjustment was based on therapeutic drug monitoring (TDM) in order to maintain trough blood concentration (C0) in the therapeutic range of 5–15 ng/mL [2]. Blood tacrolimus concentrations were measured using an enzymemultiplied immunoassay technique (EMIT). In October 2012, tacrolimus was given at the dose of 6.5 mg twice daily. As the child developed diarrhea, berberine (0.2 g three times daily) was started. Tacrolimus C0 and increased from 8 to 22 ng*mL, while serum creatinine increased from 62 to 109 μmol*L. Therefore, daily dose of tacrolimus was decreased to 3 mg and after 5 days, C0 was 12 ng*mL , while serum creatinine decreased to 84 μmol*L. The review of the medical chart did not allow identification of any other known factors (liver function, infection) that might explain such increase in tacrolimus concentrations and none of the other associated drugs are known to interact with tacrolimus metabolism and disposition. Polymorphisms of CYP3A4 (*1B), CYP3A5 (*3) and ABCB1 (C3435T) were determined using TaqMan allelic discrimination technique. Pharmacogenotyping results indicated that our patient was homozygous wild type for CYP3A4*1B, homozygous mutated (*3/*3) for CYP3A5, homozygous mutated for C3435T (T/T). To our knowledge, our report demonstrates for the first time that berberine strongly affects the disposition of tacrolimus, with clinically relevant increase in tacrolimus C0 concentrations and renal toxicity. Berberine is an inhibitor of CYP3A4. It has been reported to increase cyclosporine concentration in renal transplant adults and midazolam concentrations in adult healthy volunteers [3, 4]. The individual pharmacogenetic profile of our patient might be helpful for interpreting the significant tacrolimus–berberine interaction. This observation implies drug–drug interaction in both drug metabolism and transport. Our patient is deficient for CYP3A5 genes, CYP3A4 pathway became predominant. Furthermore, the patient was homozygous mutated C3435T (T/T) for transporter ABCB1, leading to a significantly reduced ABCB1 expression. The competition between the two drugs occurs also at the CYP3A4 pathway, resulting in high tacrolimus concentrations. We report a significant in vivo interaction between tacrolimus and berberine, both substrates of CYP3A4-A5, resulting in rapid increase in tacrolimus blood concentrations. Berberine is currently used for the treatment of diarrhea. Careful monitoring of tacrolimus blood concentrations and Q. Hou :W. Han (*) :X. Fu (*) Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China e-mail: hanwdrsw69@yahoo.com e-mail: fu_ys@yahoo.cn

Multidrug Resistance-Associated Protein 2 (MRP2/ABCC2) Haplotypes Significantly Affect the Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients

Tacrolimus is an immunosuppressive drug used for the prevention of the allograft rejection in kidney transplant recipients. It exhibits a narrow therapeutic index and large pharmacokinetic variability. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) 3A4 and 3A5 and effluxed via ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), encoded by ABCB1 gene. The influence of CYP3A5*3 on the pharmacokinetics of tacrolimus has been well characterized. On the other hand, the contribution of polymorphisms in other genes is controversial. In addition, the involvement of other efflux transporters than P-gp in tacrolimus disposition is uncertain. The present study was designed to investigate the effects of genetic polymorphisms of CYP3As and efflux transporters on the pharmacokinetics of tacrolimus. A total of 500 blood concentrations of tacrolimus from 102 adult stable kidney transplant recipients were included in the analyses. Genetic polymorphisms in CYP3A4 and CYP3A5 genes were determined. In addition, the genes of efflux transporters including P-gp (ABCB1), multidrug resistance-associated protein (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) were genotyped. For ABCC2 gene, haplotypes were determined as follows: H1 (wild type), H2 (1249G>A), H9 (3972C>T) and H12 (-24C>T and 3972C>T). Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. Analyses revealed that the CYP3A5 expressers (CYP3A5*1 carriers) and MRP2 high-activity group (ABCC2 H2/H2 and H1/H2) showed a decreased dose-normalized trough concentration of tacrolimus by 2.3-fold (p<0.001) and 1.5-fold (p=0.007), respectively. The pharmacokinetics of tacrolimus were best described using a two-compartment model with first order absorption and an absorption lag time. In the population pharmacokinetic analysis, CYP3A5 expressers and MRP2 high-activity groups were identified as the significant covariates for tacrolimus apparent clearance expressed as 20.7×(age/50)(-0.78)×2.03 (CYP3A5 expressers)×1.40 (MRP2 high-activity group). No other CYP3A4, ABCB1 or ABCG2 polymorphisms were associated with the apparent clearance of tacrolimus. This is the first report showing that MRP2/ABCC2 has a crucial impact on the pharmacokinetics of tacrolimus in a haplotype-specific manner. Determination of the ABCC2 as well as CYP3A5 genotype may be useful for more accurate tacrolimus dosage adjustment.

Prevalence of renal dysfunction in tacrolimus‐treated pediatric transplant recipients: A systematic review

Renal dysfunction after non-renal transplantation in adult tacrolimus-treated transplant patients is well documented. Little is known about its prevalence in children. Age-related changes in both disposition and effect of tacrolimus as well as renal function may preclude extrapolation of adult data to children. To systematically review the literature on renal dysfunction in non-renal pediatric transplant recipients treated with tacrolimus. PubMed/Medline, Embase, and Google were searched from their inception until April 19, 2012, with the search terms "tacrolimus," "renal function," "transplantation," and "children." Eighteen of 385 retrieved papers were considered relevant. Twelve dealt with liver, four with heart transplant, one with heart and lung transplant, and one with intestinal recipients. Reported prevalences of mild and severe chronic kidney disease ranged from 0% to 39% and 0% to 71.4%, respectively, for liver, and from 22.7% to 40% and 6.8% to 46%, respectively, for heart and/or lung transplant recipients. Ranges remained wide after adjusting for follow-up time and disease severity. Possible explanations are inclusion bias and definitions used for renal dysfunction. A considerable proportion of pediatric non-renal transplant patients who receive tacrolimus-based immunosuppression, appear to suffer from chronic kidney disease. This conclusion warrants further research into the real risk, its risk factors, and individualization of immunosuppressant therapy.

Concentration of tacrolimus and major metabolites in kidney transplant recipients as a function of diabetes mellitus and cytochrome P450 3A gene polymorphism

1. Disposition of tacrolimus and its major metabolites, 13-O-desmethyl tacrolimus and 15-O-desmethyl tacrolimus, was evaluated in stable kidney transplant recipients in relation to diabetes mellitus and genetic polymorphism of cytochrome P450 (CYP) 3A.2. Steady-state concentration–time profiles were obtained for 12-hour or 2-hour post-dose, in 20 (11 with diabetes) and 32 (24 with diabetes) patients, respectively. In addition, single nucleotide polymorphisms of the following genes: CYP3A4 (CYP3A4: CYP3A4*1B, −392A > G), 3A5 (CYP3A5: CYP3A5*3, 6986A > G) and P-glycoprotein (ABCB1: 3435C > T) were characterized.3. Dose-normalized concentrations of tacrolimus or metabolites were higher in diabetic patients. CYP3A4*1B carriers and CYP3A5 expressers, independently or when assessed as a combined CYP3A4-3A5 genotype, had significantly lower dose-normalized pre-dose (C0/dose) and 2-hour post-dose (C2/dose) concentrations of tacrolimus and metabolites. Non-diabetic patients with at least one CYP3A4*1B and CYP3A5*1 allele had lower C0/dose as compared to the rest of the population.4. Genetic polymorphism of CYP3A5 or CYP3A4 influence tacrolimus or metabolites dose-normalized concentrations but not metabolite to parent concentration ratios. The effect of diabetes on tacrolimus metabolism is subject to debate and requires a larger sample size of genetically stratified subjects.

Influence of SLCO1B3 Genetic Variations on Tacrolimus Pharmacokinetics in Renal Transplant Recipients

The immunosuppressive drug tacrolimus requires strict therapeutic monitoring due to its narrow therapeutic index and high interindividual variability. Organic anion transporting polypeptide 1B3 (OATP1B3) is a human hepatocyte transporter involved in the hepatobiliary elimination of diverse endogenous and exogenous substances. Genetic variations within the solute carrier (SLCO) 1B3 gene that encodes OATP1B3 may contribute to interindividual differences in tacrolimus disposition. The purpose of the present study is to investigate the association between SLCO1B3 polymorphisms and tacrolimus pharmacokinetics in renal transplant recipients. We found significant correlations between two linked coding nonsynomymous polymorphisms, T334G and G699A, and mean dose-adjusted tacrolimus trough blood concentrations during the first week post-transplantation (p = 0.04) and when the target dose (10-12 ng/ml) was obtained (p = 0.01). Patients carrying the homozygous mutant haplotype had 14.3-fold higher risk (95% confidence interval: 1.43-100; p = 0.02) of having blood tacrolimus concentrations above the median level, and thus being classified as poor OATP1B3 transporters, than carriers of one or two copies of the wild-type haplotype. This study shows, for the first time, that SLCO1B3 polymorphism is associated with tacrolimus exposure in the early post-transplant period.

Measurement and Compartmental Modeling of the Effect of CYP3A5 Gene Variation on Systemic and Intrarenal Tacrolimus Disposition

We evaluated the hypothesis that cytochrome P450 3A5 (CYP3A5) expression can affect intrarenal tacrolimus accumulation. Tacrolimus was administered orally to 24 healthy volunteers who were selected on the basis of their CYP3A5 genotype. As compared with CYP3A5 nonexpressors, expressors had a 1.6-fold higher oral tacrolimus clearance and 2.0- to 2.7-fold higher metabolite/parent area under the curve (AUC) ratios for 31-desmethyl tacrolimus (31-DMT), 12-hydroxy tacrolimus, and 13-desmethyl tacrolimus (13-DMT). In addition, the apparent urinary tacrolimus clearance was 36% lower in CYP3A5 expressors as compared with nonexpressors. To explore the mechanism behind this observation, we developed a semiphysiological model of renal tacrolimus disposition and predicted that tacrolimus exposure in the renal epithelium of CYP3A5 expressors is 53% of that for CYP3A5 nonexpressors, when normalized to blood AUC. These data suggest that, at steady state, intrarenal accumulation of tacrolimus and its primary metabolites will depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient differences in the risk of tacrolimus-induced nephrotoxicity.

Clinical Pharmacokinetics and Pharmacodynamics of Prednisolone and Prednisone in Solid Organ Transplantation

Prednisolone and prednisone are integral components of induction and maintenance immunosuppressive regimens in solid organ transplantation. The pharmacokinetics of these agents are extremely complex. Prednisolone is the active drug moiety while prednisone is both a pro-drug and inactive metabolite of prednisolone. Within the dosage range used in transplantation, prednisolone and prednisone exhibit concentration-dependent non-linear pharmacokinetics when parameters are measured with reference to total drug concentration. Dose dependency disappears when free (unbound) prednisolone is measured. Altered organ function, changing biochemistry and use of a number of concomitant medicines in transplantation appear to lead to pharmacokinetic differences in transplant recipients compared with other patient groups. Greater than threefold variability in dose-adjusted exposure to total prednisolone in transplant recipients is evident. Time post-transplant, hepatic and renal dysfunction, patient age, sex, bodyweight, serum albumin concentration, concomitant medication exposure, various disease states and genetic polymorphisms in metabolic enzymes and drug transporters have sometimes been associated with prednisolone pharmacokinetic variability. The clinical impact of corticosteroid therapy on the disposition of ciclosporin, tacrolimus and sirolimus and the impact of different immunosuppressant therapy combinations on prednisolone exposure needs to be further elucidated. Patient response patterns to prednisolone are consistent with delayed and indirect mechanisms of corticosteroid action involving modification of nuclear transcription and protein synthesis. Many adverse effects have been linked with prednisolone and prednisone therapy, but not all of these have been investigated thoroughly in transplant populations. Dyslipidaemia, growth restriction, diabetogenesis, hypertension and cataracts are well studied toxicities. Evidence is less clear for prednisolone-induced osteonecrosis, obesity and hypertriglyceridaemia. There have been some reports of a relationship between prednisolone pharmacokinetics and incidence of acute rejection, Cushing's syndrome and adverse cardiovascular and metabolic events. Dosing of prednisolone and prednisone in transplantation is typically empirical and varies significantly across transplant centres. Currently, authoritative guidelines are conflicting in their opinions regarding corticosteroid avoidance and early discontinuation in adult kidney transplantation. Overall, data suggest the promise of corticosteroid-free immunosuppression in paediatric patients. Further investigation of the pharmacokinetics and pharmacodynamics of prednisolone and prednisone in transplant recipients based on new chromatography assay techniques and free drug measurement, population pharmacokinetic/pharmacodynamic modelling approaches, genetic testing and larger studies in patients on modern day immunosuppressant protocols may lead to better individualization of corticosteroid therapy in the future.

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.

Tacrolimus-induced nephrotoxicity and genetic variability: A review

Calcineurin inhibition (CNI) is the mainstay of immunosuppressant therapy for most solid organ transplant patients. High tacrolimus levels are related with acute nephrotoxicity, but the relationship with chronic toxicity is less clear. Variation in disposition of tacrolimus is associated with genetic variation in CYP3A5. Hence, could genetic variation in CYP3A5 or other genes involved in tacrolimus disposition and effect be associated with a risk for tacrolimus-induced nephrotoxicity? To perform a review of the literature and to identify if genetic variation in CYP3A5 or other genes involved in tacrolimus disposition or effect may be associated with tacrolimus-induced nephrotoxicity and/or renal dysfunction in solid organ transplant recipients. Pubmed/Medline, Embase and Google were searched from their inception till November 8th 2010 with the search terms 'tacrolimus', 'genetics', and 'nephrotoxicity' or 'renal dysfunction'. References of relevant articles were screened as well. We identified 13 relevant papers. In kidney recipients, associations between donor ABCB1, recipient CCR5 genotype and tacrolimus-induced nephrotoxicity were found. CYP3A5 genotype studies in kidney recipients yielded contradictory results. In liver recipients, a possible association between recipient ACE, CYP3A5, ABCB1 and CYP2C8 genetic polymorphisms and tacrolimus-induced nephrotoxicity was suggested. In heart recipients, TGF-β genetic polymorphisms were associated with tacrolimus-induced nephrotoxicity. The quality of the studies varied considerably. Limited evidence suggests that variation in genes involved in pharmacokinetics (ABCB1 and CYP3A5) and pharmacodynamics (TGF-β, CYP2C8, ACE, CCR5) of tacrolimus may impact a transplant recipients' risk to develop tacrolimus-induced nephrotoxicity across different transplant organ groups.

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.

The interactions of age, genetics, and disease severity on tacrolimus dosing requirements after pediatric kidney and liver transplantation

PurposeIn children, data on the combined impact of age, genotype, and disease severity on tacrolimus (TAC) disposition are scarce. The aim of this study was to evaluate the effect of these covariates on tacrolimus dose requirements in the immediate post-transplant period in pediatric kidney and liver recipients.MethodsData were retrospectively collected describing tacrolimus disposition, age, CYP3A5 and ABCB1 genotype, and pediatric risk of mortality (PRISM) scores for up to 14 days post-transplant in children receiving liver and renal transplants. Initial TAC dosing was equal in all patients and adjusted using therapeutic drug monitoring. We determined the relationship between covariates and tacrolimus disposition.ResultsForty-eight kidney and 42 liver transplant recipients (median ages 11.5 and 1.5 years, ranges 1.5–17.7 and 0.05–14.8 years, respectively) received TAC post-transplant. In both transplant groups, younger children (<5 years) needed higher TAC doses than older children [kidney: 0.15 (0.07–0.35) vs. 0.09 (0.02–0.20) mg/kg/12h, p = 0.046, liver: 0.12 (0.04–0.32) vs. 0.09 (0.01–0.18) mg/kg/12h, p = 0.038]. In kidney but not liver transplants, CYP3A5 expressors needed significantly higher TAC doses than nonexpressors [0.15 (0.07–0.20) vs. 0.09 (0.02–0.35) mg/kg/12h, P = 0.001]. In these patients, age and CYP3A5 genotype were independently associated with TAC dosing requirement. In liver, but not kidney transplant patients, homozygous ABCB1 T-T-T haplotype carriers needed higher TAC doses than noncarriers [0.26 (0.15–0.32) vs. 0.11 (0.01–0.25) mg/kg/12h, p = 0.013].Conclusion CYP3A5 genotype may explain variation in tacrolimus disposition early after transplant in pediatric kidney recipients, independent of age-related variation. In contrast, in pediatric liver recipients, variation in tacrolimus disposition appears related to age and ABCB1 genotype. These findings illustrate the importance of the interplay among age, genotype, and transplant organ on tacrolimus disposition.

Gender Differences in Pharmacokinetics of Tacrolimus and Their Clinical Significance in Kidney Transplant Recipients

The possible influence of gender on tacrolimus disposition and response in kidney transplant recipients is an issue of medical importance. The aim of this study was to detect interpatient pharmacokinetic variability of tacrolimus due to patients' gender and to assess the predictability of individual tacrolimus concentrations using abbreviated AUC measurements. The secondary objective was to find the best sampling time to predict the exposure of tacrolimus in kidney transplant recipients. Gender-related first oral dose tacrolimus pharmacokinetics studies were conducted in 20 Serbian kidney transplant recipients (10 men/10 women) on quaternary immunosuppressive therapy. The first tacrolimus oral dose (0.05 mg/kg) was given on day 5 post-transplant. Blood concentrations were measured by microparticle enzyme immunoassay method. Associations between each sampling time point of concentrations and 12 hours after the administration AUC (AUC(0-12)) were evaluated by Pearson correlation coefficients. Abbreviated sampling equations were derived by multiple stepwise regression analyses. AUC(0-12) showed remarkable interindividual variations after the first tacrolimus oral dose. There were significantly lower values of AUC in women than men (P < 0.05). The most important time point influencing AUC(0-12) was the concentration of tacrolimus measured 2 hours after administration(C(2)) in women, whereas in men the most important time points were the concentrations at 1 (C(1)), 4 (C(4)), and 12 (C(12)) hours as an abbreviated AUC. Our results show significant differences between men and women. C(2) seems to be indicator of total body exposure to tacrolimus in the early period after kidney transplant in women. The three-point sampling method seems to be a good indicator of abbreviated AUC for a tacrolimus monitoring strategy in men.

A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients

Background: Tacrolimus, a calcineurin inhibitor with a macrolide lactone structure, is currently used as a cornerstone immunosuppressive drug in solid organ transplantation. It is metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A4/3A5 enzymes and is a substrate for P-glycoprotein (ABCB1). The disposition of tacrolimus might be influenced by severe renal allograft dysfunction (eg, in cases of delayed graft function [DGF]). New-onset diabetes after transplantation (NODAT) is a known adverse effect of tacrolimus therapy and has been associated with DGF. Objectives: The impact of DGF on tacrolimus C min and dose requirements was evaluated in renal transplant recipients in the first postoperative week. The effects of the CYP3A5*3 A6986G polymorphism on initial mean tacrolimus C min and dose requirements in the presence and absence of DGF were assessed. This study also tested the hypothesis that if DGF influences early tacrolimus exposure, this would lead to a higher risk for NODAT (defined as the need for glucose-lowering medication for an uninterrupted period of ≥26 weeks). Methods: This prospective, open-label, observational clinical cohort study enrolled renal allograft recipients aged ≥18 years. Tacrolimus was administered as an oral loading dose of 0.2 mg/kg/d and adjusted to achieve a target mean daily tacrolimus C min between 12 and 15 ng/mL. C min values and oral dose requirements in the first postoperative week were compared between patients with and without DGF. Patients were genotyped for the CYP3A4*1B -290A>G, CYP3A5*3 A6986G, ABCB1 Exon26 C3435T, ABCB1 Exon21 G2677T, and ABCB1 Exon21 G2677A single nucleotide polymorphisms. NODAT that occurred within the first 12 weeks after transplantation was confirmed using an oral glucose tolerance test. Results: A total of 304 patients were enrolled (184 men, 120 women; mean [SD] age, 52.9 [14.1] years). Through day 3 after transplantation, mean (SD) 12-hour tacrolimus C min values were significantly higher in recipients experiencing DGF despite identical loading doses of 0.2 mg/kg. Mean tacrolimus dose requirements were significantly lower in patients with DGF during the first week. After recovery of DGF, mean tacrolimus dose requirements were not significantly different between recipients with and without DGF. In homozygous CYP3A5*3 carriers (n = 252), mean (SD) tacrolimus dose requirements remained significantly lower during DGF, while in CYP3A5*1 carriers with DGF (n = 52), lower mean dose requirements were observed only after postoperative day 4. The proportion of patients in whom NODAT developed was significantly greater in patients with DGF and tacrolimus C min >15 ng/mL on the first day after transplantation (27.2%) compared with recipients who remained free of DGF and had Cmin ≤15 ng/mL on day 1 (6.5%) ( P = 0.016). On logistic regression analysis, greater recipient age (odds ratio [OR] = 1.044; 95% CI, 1.009–1.080), higher tacrolimus C min on day 1 (OR = 1.048; 95% CI, 1.017–1.080), and DGF (OR = 2.968; 95% CI, 1.107–7.959) were associated with an increased risk for NODAT. Conclusion: In this open-label, observational study, DGF was associated with higher initial mean tacrolimus Cmin values and lower daily dose requirements predominantly in CYP3A5 nonexpressers.