Affect Tacrolimus Pharmacokinetics Research Articles

Genotype-Guided Model for Prediction of Tacrolimus Initial Dosing After Lung Transplantation.

The determination of the appropriate initial dose for tacrolimus is crucial in achieving the target concentration promptly and avoiding adverse effects and poor prognosis. However, the trial-and-error approach is still common practice. This study aimed to establish a prediction model for an initial dosing algorithm of tacrolimus in patients receiving a lung transplant. A total of 210 lung transplant recipients were enrolled, and 26 single nucleotide polymorphisms (SNP) from 18 genes that could potentially affect tacrolimus pharmacokinetics were genotyped. Associations between SNPs and tacrolimus concentration/dose ratio were analyzed. SNPs that remained significant in pharmacogenomic analysis were further combined with clinical factors to construct a prediction model for tacrolimus initial dose. The dose needed to reach steady state tacrolimus concentrations and achieve the target range was used to validate model prediction efficiency. Our final model consisted of 7 predictors-CYP3A5 rs776746, SLCO1B3 rs4149117, SLC2A2 rs1499821, NFATc4 rs1955915, alanine aminotransferase, direct bilirubin, and hematocrit-and explained 41.4% variance in the tacrolimus concentration/dose ratio. It achieved an area under the receiver operating characteristic curve of 0.804 (95% confidence interval, 0.746-0.861). The Hosmer-Lemeshow test yielded a nonsignificant P value of .790, suggesting good fit of the model. The predicted dose exhibited good correlation with the observed dose in the early postoperative period (r=0.748, P less than .001). Our study provided a genotype-guided prediction model for tacrolimus initial dose, which may help to guide individualized dosing of tacrolimus in the lung transplant population in clinical practice.

Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study.

Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis. A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.

GRWR Correlates with the Metabolism of Tacrolimus after Pediatric Living Donor Liver Transplantation According to Donor CYP3A5 Polymorphism

Tacrolimus is characterized by high pharmacokinetic variability in combination with a narrow therapeutic range. However, influence of donor CYP3A5 genotype and graft-to-recipient body weight ratio (GRWR) on tacrolimus' pharmacokinetics after pediatric living donor liver transplantation (LDLT) remains unclear. A total of 174 LDLT recipients (<6 y) were grouped according to donor CYP3A5 genotypes (nonexpressor (NEX) or expressor (EX)) and GRWR (<3.0% (SS, small-size) or ≥3.0% (LS, large-size)): SS/NEX (n = 40), SS/EX (n = 38), LS/NEX (n = 48), and LS/EX (n = 48). Pharmacokinetics of tacrolimus and clinical outcomes were analyzed. The relationships between the concentration-dose ratio and donor CYP3A5 genotypes and graft size were examined 3, 7, 14, and 30 days after the transplantation. Tacrolimus C0 levels varied greatly among groups, although recipients started with the same initial dosage. LS/EX recipients had significantly lower C0 levels in comparison with those of other groups. The use of CYP3A5-EX-grafts and a greater GRWR both resulted in significantly higher TAC dose requirements and lower C/D ratios. However, the significance of GRWR no longer exists 3 months after transplantation. The multivariate generalized linear mixed model analysis showed that donor CYP3A5 genotypes (F = 11.876; P = 0.01) and GRWR (F = 4.631; P = 0.033) were independent impact factors for C/D ratios 3, 7, 14, and 30 days after transplantation. Donor CYP3A5-EX genotype was associated with significantly increasing risks of infectious complications and significantly lower Cylex ATP values. However, no significant difference was observed in acute rejections among 4 groups. Monitoring of C0 levels alone is not reliable to guide tacrolimus administration. Donor CYP3A5 and GRWR both significantly affect tacrolimus pharmacokinetics after pediatric LDLT. The use of Cylex ATP tests would be helpful to avoid overimmunosuppression.

The Impact of CYP3A4*22 on Tacrolimus Pharmacokinetics and Outcome in Clinical Practice at a Single Kidney Transplant Center.

Background: Although there is evidence that the CYP3A4*22 variant should be considered in tacrolimus dosing in renal transplantation, its impact beyond tacrolimus dose requirements remains controversial.Methods: In a cohort of 121 kidney transplant recipients, we analyzed the CYP3A4*1B, CYP3A4*22, and CYP3A5*3 alleles and the ABCB1 variants 1236C>T, 2677G>T/A, and 3435C>T for their impact on exposure and dose requirement. Relevant clinical outcome measures such as acute rejection within the first year after transplantation, delayed graft function, and renal function at discharge (estimated glomerular filtration rate) were evaluated.Results: Extensive metabolizer (n = 17, CYP3A4*1/*1 carriers with at least one CYP3A5*1 allele) showed significantly higher tacrolimus dose requirement (P = 0.004) compared with both intermediate metabolizer (IM, n = 93, CYP3A5*3/*3 plus CYP3A4*1/*1 or CYP3A4*22 carriers plus one CYP3A5*1 allele), and poor metabolizer (n = 11, CYP3A4*22 allele in combination with CYP3A5*3/*3) after onset of therapy. Significantly higher dose requirement was observed in CYP3A5 expressers (P = 0.046) compared with non-expressers again at onset of therapy. Using the log additive genetic model, the area under the curve for the total observation period up to 16 days was significantly associated with the CYP3A5*3 genotype (P = 3.34 × 10-4) as well as with the IM or extensive metabolizer phenotype (P = 1.54 × 10-4), even after adjustment for multiple testing. Heterozygous carriers for CYP3A4*22 showed significantly higher areas under the curve than the CYP3A4*1/*1 genotype in the second week post-transplantation (adjusted P = 0.016). Regarding clinical outcomes, acute rejection was significantly associated with human leukocyte antigen mismatch (≥3 alleles; OR = 12.14, 95% CI 1.76, 525.21, P = 0.019 after correction for multiple testing). Graft recipients from deceased donors showed higher incidende of delayed graft function (OR 7.15, 95% CI 2.23, 30.46, adjusted P = 0.0008) and a lower estimated glomerular filtration rate at discharge (P = 0.0001). Tested CYP3A4 or CYP3A5 variants did not show any effects on clinical outcome parameters. ABCB1 variants did neither impact on pharmacokinetics nor on clinical endpoints.Conclusion: At our transplantation center, both CYP3A5*3 and, to a lesser extent, CYP3A4*22 affect tacrolimus pharmacokinetics early after onset of therapy with consequences for steady-state treatment in routine clinical practice.

A Minimal Physiologically-Based Pharmacokinetic Model for Tacrolimus in Living-Donor Liver Transplantation: Perspectives Related to Liver Regeneration and the cytochrome P450 3A5 (CYP3A5) Genotype.

In adult patients after living‐donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically‐based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living‐donor liver transplantation. The clearance was about 1.35‐fold higher in the recipients who had a liver with the CYP3A5*1 allele than in those with the CYP3A5*3/*3 genotype, whereas bioavailability was ~0.7‐fold higher in the recipients who had intestines with the CYP3A5*1 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically‐based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.

Impact of CYP3A5, POR, and CYP2C19 Polymorphisms on Trough Concentration to Dose Ratio of Tacrolimus in Allogeneic Hematopoietic Stem Cell Transplantation.

Single nucleotide polymorphisms in drug-metabolizing genes may affect tacrolimus pharmacokinetics. Here, we investigated the influence of genotypes of CYP3A5, CYP2C19, and POR on the concentration/dose (C/D) ratio of tacrolimus and episodes of acute graft-versus-host disease (GVHD) in Japanese recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Thirty-six patients receiving the first HSCT using tacrolimus-based GVHD prophylaxis were enrolled with written informed consent. During continuous intravenous infusion, HSCT recipients carrying the CYP3A5*1 allele, particularly those with at least one POR*28 allele, had a significantly lower tacrolimus C/D ratio throughout all three post-HSCT weeks compared to that in recipients with POR*1/*1 (p < 0.05). The CYP3A5*3/*3 genotype and the concomitant use of voriconazole were independent predictors of an increased tacrolimus C/D ratio during the switch from continuous intravenous infusion to oral administration (p < 0.05). In recipients receiving concomitant administration of voriconazole, our results suggest an impact of not only CYP3A5 and CYP2C19 genotypes, but also plasma voriconazole concentration. Although switching from intravenous to oral administration at a ratio of 1:5 was seemingly appropriate in recipients with CYP3A5*1, a lower conversion ratio (1:2–3) was appropriate in recipients with CYP3A5*3/*3. Our results suggest that CYP3A5, POR, and CYP2C19 polymorphisms are useful biomarkers for individualized dosage adjustment of tacrolimus in HSCT recipients.

The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients.

Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients.We aim to investigate the effects of cytochrome P450 (CYP)3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6months after heart transplantion to evaluate acute rejection degrees. All participants were then followed upannually until May 2018.The designed primary endpoint was all-cause mortality. In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6months after heart transplantion. The median follow-up period was 94.7months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

Impact of FOXP3 Polymorphisms on the Blood Level of Tacrolimus in Renal Transplant Recipients.

Tacrolimus is an immunosuppressive medication for organ transplantation. FOXP3(+) T regulatory cells (Tregs) play roles in suppression of rejection and induction of graft tolerance. This study aimed to evaluate the correlation between the polymorphism of FOXP3 and the blood level of tacrolimus in renal transplant recipients. This retrospective study included 100 renal transplant recipients receiving tacrolimus treatment and 100 healthy control subjects. Genotyping for FOXP3 rs3761547 AA, AG, GG, rs3761548 AA, AC, CC and rs223236 AA, AG, GG was performed. Concentrations of tacrolimus, creatinine, and urea nitrogen levels in blood were measured. Frequencies of genotypes of FOXP3 rs3761548 AA, AC, and CC, rs3761547 AA, AG, GG and rs 223236 AA, AG, GG in renal transplant recipients were similar to those in normal people. The blood level of tacrolimus in recipients with rs3761548 CC was significantly higher than that in recipients with rs3761548 AA and AC (P< .001). No difference in the blood level of tacrolimus was found in recipients with different genotypes of rs3761547 and rs223236. Compared to rs3761548 AA and AC groups, there was no difference of Modification of Diet in Renal Disease (MDRD) glomerular filtration rate and the level of blood urea nitrogen before transplantation; however, these 2 parameters were significantly improved after transplantation in the rs3761548 CC group. The level of tacrolimus was correlated positively with MDRD glomerular filtration rate and negatively with the blood urea nitrogen level in recipients with rs3761548 CC genotype after transplantation. Our study identified a new relationship between FOXP3 rs3761548 and the blood level of tacrolimus. These results suggest that the polymorphism of FOXP3 may affect tacrolimus pharmacokinetics.

Population Pharmacokinetic Analysis of Tacrolimus in Adult Mexican Patients with Renal Transplant

The aim of this study was to estimate the population pharmacokinetic parameters of Tacrolimus in Mexican adults undergoing kidney transplantation and to identify the clinical factors affecting Tacrolimus pharmacokinetics. Using Non-linear mixed effects modeling (NONMEM) with First-order absorption and elimination, a total of 592 retrospective-prospective drug monitoring data points were collected from 36 patients with renal transplant receiving Tacrolimus (Prograf® twice daily during the first 6 post-transplantation months and a generic product thereafter. The absorption rate constant was fixed at 4.5 h –1 , and the following population pharmacokinetic estimates were obtained: Tacrolimus clearance (CL/F), 22.5 L/h, and apparent volume of distribution (V/F), 812 L. Interindividual variability was 52.9 and 82.1% for CL/F and V/F, respectively. The covariates that significantly affect Tacrolimus pharmacokinetics parameters were concomitantly administered calcium channel blocker drug and hematocrit level. The population pharmacokinetic analysis identified important sources of variability in Tacrolimus pharmacokinetics. The model will help to calculate Tacrolimus dose requirements in Mexican renal transplant recipients according to specific clinical factors affecting Tacrolimus clearance and volume of distribution and it will also be useful for therapeutic drug monitoring.

Which Genetic Determinants Should be Considered for Tacrolimus Dose Optimization in Kidney Transplantation? A Combined Analysis of Genes Affecting the CYP3A Locus.

Tacrolimus is established as immunosuppressant after kidney transplantation. Polymorphism of the cytochrome P450 3A5 (CYP3A5) gene contributes significantly to tacrolimus dose requirements. Recently, CYP3A4*22 was reported to additionally affect tacrolimus pharmacokinetics (PK). In addition, there are further polymorphic genes, possibly influencing CYP3A activity [pregnane x receptor NR1I2, P450 oxidoreductase (POR), and peroxisome proliferator-activator receptor alpha (PPARA)]. We aimed to investigate combined effects of these gene variants on tacrolimus maintenance dose and PK in patients with stable kidney transplantation of 2 study centers. A total of 223 white patients (German cohort, 136; Danish cohort, 87) was included and genotyped for CYP3A5 (rs776746), CYP3A4 (rs35599367), NR1I2 (rs2276707), POR (rs1057868), and PPARA (rs4253728). Dosage and trough concentration/dose ratios were considered separately. A subset was investigated for comprehensive PK parameters. Tacrolimus dose, trough concentration, and trough concentration/dose ratio did not differ between the German and Danish cohort. CYP3A5*3 and CYP3A4*22 contributed to dose requirements only in the German and in the total cohort. Homozygous carriers of both variants required 4.8 ± 3.1 mg, whereas carriers of the wild types required 165% higher mean tacrolimus doses (12.5 ± 7.7 mg, P = 1.4 × 10). The PK investigation revealed only nonsignificant impact of CYP3A4 genotypes on AUC12h in CYP3A5 nonexpressers (P = 0.079, power = 57%). For the entire sample, the final multiple linear regression model for trough concentration/dose ratio included CYP3A5, CYP3A4, and age. It explained 18.3% of the interindividual variability of tacrolimus trough concentration/dose ratios (P = 8.8 × 10). Therapeutic drug monitoring remains essential in clinical care of patients with kidney transplantation. Genotyping of CYP3A5 and CYP3A4, however, could facilitate rapid dose finding to adapt the appropriate immunosuppressant dose, whereas other genetic factors had only little or no effect.

Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies.

The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.

PKP-001 Tacrolimus plasma levels in adults during haematopoietic stem cell allotransplantation

BackgroundWhen an unrelated donor is used for an allogeneic hematopoietic stem cell transplant (AlloHSCT) highly immunosuppressive treatment is needed during the early post-transplant period as prophylaxis against acute graft versus...

Population Pharmacokinetic–Pharmacogenetic Model of Tacrolimus in the Early Period after Kidney Transplantation

As tacrolimus has a rather narrow therapeutic range and high individual variability in its pharmacokinetics, it is important to determine the cause of the variation in tacrolimus pharmacokinetics. The purpose of this study was to establish a population pharmacokinetic-pharmacogenetic model of tacrolimus and identify covariates that affect pharmacokinetic parameters to prevent fluctuations in the tacrolimus trough concentration during the early period after transplantation. Data from 1501 trough concentrations and 417 densely collected concentrations were compiled from 122 patients who were on post-operative days 10-20 and analysed with a nonlinear mixed-effect model. The first-order conditional estimation (FOCE) with interaction method was used to fit the model using the NONMEM program. Clinical/laboratory data were also collected for the same period, and CYP3A5 and ABCB1 genotypes were analysed for use in modelling from all included patients. An empirical Bayesian approach was used to estimate individual pharmacokinetic profiles. A one-compartment model with first absorption and elimination and lag time best described the data. The estimated population mean of clearance (CL/F), volume of distribution (V/F) and absorption rate (Ka ) were 21.9L/hr, 205L, and 3.43/hr, respectively, and the lag time was fixed at 0.25hr. Clearance increased with days after transplantation and decreased with CYP3A5*3/*3 about 18.4% compared with CYP3A5*1 carriers (p<0.001). A population pharmacokinetic model was developed for tacrolimus in early post-kidney transplantation recipients to identify covariates that affect tacrolimus pharmacokinetics. Post-operative days and CYP3A5 genotype were confirmed as critical factors of tacrolimus pharmacokinetics.

The P450 Oxidoreductase *28 SNP is Associated with Low Initial Tacrolimus Exposure and Increased Dose Requirements in CYP3A5-Expressing Renal Recipients

Recently a SNP of the gene encoding P450 oxidoreductase (POR*28; rs1057868C>T) has been associated with increased in vivo CYP3A activity using midazolam as a drug probe. Because tacrolimus is metabolized by CYP3A isoenzymes, this SNP might affect tacrolimus pharmacokinetics. To test this hypothesis we performed a study in a cohort of 298 de novo renal allograft recipients stratified according to CYP3A5 genotype, which has a known impact on tacrolimus pharmacokinetics. We found that in CYP3A5 expressers (CYP3A5*1 allele carriers) receiving a standard loading dose of 0.2 mg/kg, POR*28T allele carriers had lower tacrolimus C₀ levels in the first days post-transplantation and reached target C₀ levels significantly later as compared with POR*28CC homozygous patients. The POR*28T allele carriers had significantly higher tacrolimus dose requirements throughout the first year. In CYP3A5 nonexpressers (CYP3A5*3/*3) the POR*28 SNP did not affect tacrolimus pharmacokinetics. These data indicate that the POR*28 SNP is associated with additional increases in early tacrolimus dose-requirements in patients carrying a CYP3A5*1 allele.

Different Influences on Tacrolimus Pharmacokinetics by Coadministrations of Zhi Ke and Zhi Shi in Rats

Tacrolimus, an immunosuppressant with narrow therapeutic window, has been used widely in transplant patients. Grapefruit juice and pomelo have been reported to increase the blood levels of tacrolimus. Zhi Ke and Zhi Shi, the ripe peels and unripe fruits of Citrus aurantium which is chemotaxonomically related to grapefruit and pomelo, are in wide use in clinical Chinese medicine. To investigate the possible interaction of these two Citrus herbs with tacrolimus, male Sprague-Dawley rats were orally given tacrolimus (1.5 mg/kg) with and without Zhi Ke and Zhi Shi decoctions in a cross-over design. Blood samples were withdrawn via cardiopuncture at specific time and quantitated by a microparticle enzyme immunoassay. In addition, to explore the mechanism of interaction, LS 180 cell line was used for the transport study of rhodamine 123, a typical substrate of P-glycoprotein (P-gp). The results showed that Zhi Shi significantly decreased the C max and AUC0−t of tacrolimus by 72.4% and 72.0%, respectively, whereas Zhi Ke did not affect tacrolimus pharmacokinetics. LS 180 cell line study indicated that Zhi Shi increased the efflux activity of P-gp, enabling us to explain the decreased oral bioavailability of tacrolimus caused by Zhi Shi. Hence, we suggest that Zhi Shi be contraindicated for transplant patients treated with tacrolimus to reduce the risk of allograft rejection.