THE COMPARISON OF THE AFFINITY COLUMN-MEDIATED IMMUNOASSAY METHOD AND THE MICROPARTICLE ENZYME IMMUNOASSAY METHOD AS A TACROLIMUS CONCENTRATION ASSAY IN EARLY POST-LIVER-TRANSPLANTATION PERIOD
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Huh, K. H.1; Ju, M. K.2; Joo, D. J.3; Choi, J. S.3; Kim, M. S.3; Kim, S. I.3 Author InformationKeywords:
Microparticle
Tacrolimusë ì ì¥ì´ì í ë°ìí ë¶ëª ì´ìì ë°ì´ì ì ì¸ì´ ë ì ììì ê³ ë ¤í´ì¼ íë¤. ê·¸ë¬ë tacrolimus ì ë° ë° ì´ì ì§ë¨í기ì ìì ê°ì¼ì±, ìê°ë©´ìì± ë° íìì ì ê°ì ë¤ë¥¸ ì½ì ìì¸ì ëí´ì ë°°ì í´ì¼ë§ íë¤. ì ìë¤ì ì ì¥ ì´ì í ë°ìí ë°ì´ìì tacrolimus를 ì¤ë¨íê³ cyclosporine ì¼ë¡ ë³ê²½ í 24ìê° ì´ë´ ë°ì´ì´ í¸ì ë ì¦ë¡ë¥¼ ê²½ííì¬ ë³´ê³ íë ë°ì´ë¤. ì¤ì¬ ë¨ì´: íí¬ë¡ë¦¬ë¬´ì¤; ë°ì´; ì ì¥ì´ì
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Therapeutic Drug Monitoring
Blood concentration
Therapeutic index
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Background and Purpose: Several formulations of tacrolimus are available, but evidence of the benefit of changing to the most recent formulations is lacking. Tacrolimus intra-patient variability (tacrolimus IPV) is an emerging risk factor associated with poor graft outcomes after solid organ transplantations. Here, we examined the modifications of tacrolimus IPV after switching to a different formulation of tacrolimus. Experimental Approach: We identified 353 solid organ transplant recipients that were switched in our center from immediate-release (IR-tacrolimus) or prolonged-release tacrolimus (PR-tacrolimus) to extended-release, LCP-tacrolimus (LCP-tacrolimus). Among them, 54 patients underwent at least 3 available tacrolimus blood concentrations before and after the switch, allowing us to investigate tacrolimus IPV. Key Results: The switch was considered as a safe procedure since only four of the 353 patients presented a graft rejection after the switch, and no patient was hospitalized for tacrolimus overdose. The tacrolimus IPV estimated by the coefficient of variation (CV-IPV) was stable before and after the switch to LCP-tacrolimus (CV-IPV: 29.0% (IQR 25–75 (15.5; 38.5) before and 24.0% (15.8; 36.5) after the switch, p = 0.65). Conclusion and Implications : Switching from IR- or PR-tacrolimus to LCP-tacrolimus is a safe procedure. However, the CV-tacrolimus IPV was not impacted by the change of formulation.
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A simple and extensively applicable technique of fabricating microparticle layers was developed. Pure microparticle layers can be formed by annealing microparticle/polymer composite sheets on targets. During the annealing process, the polymer is pyrolytically decomposed and evaporated from the composite sheets. As a result, a layer consisting entirely of microparticles is formed on the target. Using this technique, silicon carbide whiskers and diamond microparticle layers were successfully fabricated on Si wafers.
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我们寻求了与生活施主肝移植(LDLT ) 评估低剂量的 tacrolimus (FK506 ) 的功效和效果到接受者。经历了在 2001 和 2007 之间的 LDLT 的 66 个病人的一个总数在这研究被注册。根据 tacrolimus 的不同剂量，接受者随机被划分成二个组：低剂量的 tacrolimus 组(组 A ) 和正常剂量的 tacrolimus 组(组 B ) 。包括感染，多糖症，高血压，高血 creatinine 和黄疸的 tacrolimus 和它的副作用的血集中在 perioperative 经期每周一次被监视，并且一次一个月此后。而且，接受者的幸存率在操作以后在 1 年、 3 年的时间点被分析。在这些病人之中，没有重要尖锐拒绝在 LDLT 以后被检测。在组 A 的感染，多糖症，肝机能障碍和肾的缺陷的发生是比在组 B 的那些显著地低的。然而，没有重要差别在在二个组之间的高血压的发生被检测。而且，在每个组的接受者让类似的幸存根据 1 年、 3 年的后续的结果评价。断然与 tacrolimus 联系了的副作用的发生与 tacrolimus 血集中相关。在结论， tacrolimus 的长期、低剂量的管理是为 LDLT 接受者的安全、有效的治疗。
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A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long-term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate-release (IR)-tacrolimus to either extended-release (ER)-tacrolimus or LifeCyclePharma (LCP)-tacrolimus. In this randomized, prospective, open-label, cross-over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR-tacrolimus, were randomized for conversion to ER-tacrolimus or LCP-tacrolimus, and for the order in which IR-tacrolimus and the once-daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety-two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR-tacrolimus (16.6%) and the combined once-daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] -1.1% to -4.5%, p = 0.24). The IPV of LCP-tacrolimus (20.1%) was not significantly different from the IPV of ER-tacrolimus (16.5%, % difference +3.6%, 95% CI -0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR-tacrolimus to either ER-tacrolimus or LCP-tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice-daily (IR) tacrolimus formulations to once-daily (modified-release) tacrolimus formulations when the aim is to lower the IPV.
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Therapeutic drug monitoring is routinely performed to maintain optimal tacrolimus concentrations in kidney transplant recipients. Nonetheless, toxicity and rejection still occur within an acceptable concentration-range. To have a better understanding of the relationship between tacrolimus dose, tacrolimus concentration, and its effect on the target cell, we developed functional immune tests for the quantification of the tacrolimus effect. Twelve healthy volunteers received a single dose of tacrolimus, after which intracellular and whole blood tacrolimus concentrations were measured and were related to T cell functionality. A significant correlation was found between tacrolimus concentrations in T cells and whole blood concentrations (r = 0.71, p = 0.009), while no correlation was found between tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) and whole blood (r = 0.35, p = 0.27). Phytohemagglutinin (PHA) induced the production of IL-2 and IFNγ, as well as the inhibition of CD71 and CD154 expression on T cells at 1.5 h post-dose, when maximum tacrolimus levels were observed. Moreover, the in vitro tacrolimus effect of the mentioned markers corresponded with the ex vivo effect after dosing. In conclusion, our results showed that intracellular tacrolimus concentrations mimic whole blood concentrations, and that PHA-induced cytokine production (IL-2 and IFNγ) and activation marker expression (CD71 and CD154) are suitable readout measures to measure the immunosuppressive effect of tacrolimus on the T cell.
Immunosuppressive drug
Ex vivo
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The performance of the first- and second-generation microparticle enzyme immunoassays for tacrolimus (Tacrolimus I and Tacrolimus II, respectively) was compared during 8 months routine drug monitoring. The minimum detection limit of the Tacrolimus II assay was lower: 1.4 versus 4.0 microg tacrolimus/l. There was also no overlap between results using 10 samples containing 0 and 1 microg tacrolimus/l in the Tacrolimus II assay (p < 0.001), with a corresponding significant difference achieved for the Tacrolimus I assay only at 0 and 4 microg/l. For control specimens, within-assay precision was superior for Tacrolimus II at 5 microg/l (7.3% vs. 31.5%), similar at 10 and 15 microg/l (6.3% versus 6.6% and 4.4% vs. 4.6%, respectively) but worse than Tacrolimus I at 25 microg/l (8.0% vs. 4.0%). Using three pools of blood samples from recipients of liver transplants (containing approximately 4, 10, and 20 microg tacrolimus/l) interassay precision (n > 20) was 14.2%, 10.4%, and 8.0% for Tacrolimus II and 42.4%, 13.8%, and 7.1%, for Tacrolimus I. The analytical times and stability of the calibration curves were similar for the two assays. Tacrolimus I and Tacrolimus II results were closely correlated using patients' blood samples (r approximately equal to 0.8 in 249 adult and 168 pediatric liver transplant samples, 161 renal transplant samples, and 61 samples from patients with autoimmune diseases). However, Tacrolimus II assay results were consistently lower (by a mean of 1.02 to 2.05 microg/l). The authors conclude that the Tacrolimus II assay retains the speed, accuracy, and precision of its predecessor and demonstrates an improved sensitivity, which should facilitate monitoring at less than 5 microg tacrolimus/l.
Therapeutic Drug Monitoring
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AIM: To monitor the concentration of tacrolimus in whole blood in liver transplant recipients and establish an optimal therapeutic window of tacrolimus, in order to provide information for rational usage in clinic. METHODS: The whole blood concentrations of tacrolimus were measured by ELISA. The levels of tacrolimus in 1190 samples from 138 liver transplant recipients were compared and studied. RESULTS: The whole blood concentration of tacrolimus is gradually decreased with time after operation. The optimal therapeutic window of tacrolimus for liver transplant recipients was 8-15 μg·L -1 within 1 month after operation, 6-12 μg·L -1 from the 2nd to 3rd months, 5-10 μg·L -1 from the 4th to 6th months and 3-8 μg·L -1 after 6 months, respectively. CONCLUSION: It is necessary to routinely monitor blood concentration of tacrolimus. The satisfying therapeutic effects will be obtained if dosage regimens will be individualized according to optimal therapeutic window.
Therapeutic window
Therapeutic Drug Monitoring
Blood concentration
Therapeutic effect
Therapeutic index
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