Clinical Utility of Monitoring Tacrolimus Blood Concentrations in Liver Transplant Patients

Venkataramanan, Raman; Shaw, Leslie M.; Sárközi, László; Mullins, Richard E.; Pirsch, John D.; MacFarlane, Gordon D.; Scheller, Dan; Ersfeld, Diana L.; Frick, Mary; Fitzsimmons, William E.; Virji, Mohamed A.; Jain, Ashok; Brayman, Kenneth L.; Shaked, Abraham

doi:10.1177/00912700122010429

Cited by 147 publications

(93 citation statements)

References 20 publications

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“…Tacrolimus blood concentrations are increased by inhibitors of CYP3A (ketoconazole, itraconazole, fluconazole, verapamil, diltiazem, erythromycin) and decreased by inducers of CYP3A. 8,[11][12][13] Recently, profound interactions between tacrolimus and sirolimus with various protease inhibitors have been reported. [2][3][4]12,[14][15][16] Protease inhibitors are known inhibitors of CYP3A and p-glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

Jain

Venkataramanan

Eghtesad

et al. 2003

Liver Transplantation

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With the advent of highly active antiretroviral therapy (HAART), HIV positivity is no longer a contraindication for liver transplantation. Some of the antiretroviral agents, particularly protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir) have been described as potent inhibitors of the metabolism of certain immunosuppressive drugs. In this article we describe a profound interaction between tacrolimus and Kaletra (Abbott Laboratories, Chicago, IL) (a combination of lopinavir and ritonavir) in 3 liver transplantation patients. Patient 1, who was maintained on a 5 mg twice daily dose of tacrolimus with a trough blood concentration around 10.6 ng/mL, required only 0.5 mg of tacrolimus per week after addition of Kaletra to achieve similar tacrolimus blood concentrations, with a half-life of 10.6 days. In patient 2, the area under the blood concentration versus time curve for tacrolimus increased from 31 ng/mL/h to 301 ng/mL/h after addition of Kaletra, with a corresponding half-life of 20 days. When the patient was subsequently switched to nelfinavir, the half-life decreased to 10.3 days. Patient 3, who was maintained with 4 to 8 mg/d of tacrolimus and a corresponding blood concentration of 10 ng/mL before Kaletra, required a tacrolimus dose of 1 mg/wk and tacrolimus concentrations of 5 ng/mL with Kaletra. In conclusion, a combination of lopinavir and ritonavir led to a much more profound increase in tacrolimus blood concentrations than use of single protease inhibitor, nelfinavir. A tacrolimus dose of less than 1 mg/wk may be sufficient to maintain adequate blood tacrolimus concentrations in patients on Kaletra. Patients may not need a further dose of tacrolimus for 3 to 5 weeks depending on liver function when therapy with Kaletra is initiated. Great caution is required in the management of tacrolimus dosage when Kaletra is introduced or withdrawn in HIV-positive patients after liver transplantation, particularly in the presence of hepatic dysfunction. (Liver Transpl 2003;9:954-960.)

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Section: Discussionmentioning

confidence: 99%

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

Jain

Venkataramanan

Eghtesad

et al. 2003

Liver Transplantation

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“…The narrow therapeutic margin of tacrolimus puts transplant patients at risk of overimmunosuppression with associated toxicity or inadequate immunosuppression resulting in episodes of rejection. 12 Understanding the pharmacokinetics of tacrolimus has allowed the development of dosing protocols based on blood level monitoring. However, even with strict adherence to the protocols, the blood concentration of tacrolimus poorly correlates with the dosage because of interpatient and intrapatient variability in absorption, distribution, and elimination; therefore, it is mandatory to follow the drug concentration.…”

Section: Discussionmentioning

confidence: 99%

“…For the same reasons, the rate of tacrolimus blood concentration rise is impossible to predict as well. Tacrolimus is extensively metabolized in the liver by the cytochrome P450 3A enzymes 12 ; hence, liver (allograft) metabolic function has a significant impact on the drug's pharmacokinetics. 3 The very early diagnosis of allograft dysfunction following OLT remains a significant area of interest.…”

Section: Discussionmentioning

confidence: 99%

“…This fact may have significant importance because there is strong evidence that there is an inverse relationship between increased tacrolimus serum trough levels and a decreased risk of acute rejection postoperatively. 12 In this study, postoperative liver biopsy results were evaluated for all patients; however, ICG-PDR k values above normal did not predict the presence of acute rejection. This lack of correlation is likely related to the relatively small study population and even smaller subgroup of patients exhibiting supranormal k values.…”

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confidence: 84%

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Predicting immunosuppressant dosing in the early postoperative period with noninvasive indocyanine green elimination following orthotopic liver transplantation

et al. 2007

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Twenty adult patients undergoing orthotopic liver transplantation (OLT) were enrolled in this study, with the noninvasive indocyanine green plasma disappearance rate (ICG-PDR) measured both during and after OLT to assess the relationship between ICG-PDR and the ability of patients to achieve therapeutic postoperative tacrolimus immunosuppressant blood levels. Liver function was determined at both 2 and 18 hours post reperfusion with the ICG-PDR k value (1/min). Postoperative standard serum measures of liver function as well as liver biopsies were also collected and analyzed. The median ICG-PDR k value for the study group at 2 hours post reperfusion was 0.20 (0.16, 0.27), whereas at 18 hours post reperfusion, it was 0.22 (0.18, 0.35). The median change in the k value between the two ICG-PDR measurements was 0.05 (Ϫ0.02, 0.07) with P ϭ 0.02. There was an interaction between the postoperative day 1 (18 hours post reperfusion) ICG-PDR k value and the linear increase in the tacrolimus blood level, such that the greater the k value was, the more gradual the observed rise was in tacrolimus over time [that is, the longer it took to achieve a therapeutic blood level (Ͼ12 ng/mL), P ϭ 0.003]. Of the 16 patients that received tacrolimus, comparable dosing on a per kilogram body weight basis was observed. Also, no significant association between ICG-PDR k values and postoperative liver biopsy results was seen. This study demonstrates that the ICG-PDR measurement is a modality with the potential to assist in achieving adequate blood levels of tacrolimus following OLT. Liver Transpl 14: [46][47][48][49][50][51][52] 2008. © 2007 AASLD.Received April 20, 2007; accepted July 31, 2007. Postoperative liver allograft function can significantly influence immunosuppressant levels, and as a result, frequent dosing changes of these agents are often required. Common immunosuppressive agents including cyclosporine, tacrolimus, and sirolimus are frequently dose-adjusted, as determined by measurements of whole blood concentration. In addition, these agents are principally metabolized by hepatic cytochrome enzymes, which are variably affected by age, blood flow, ischemia reperfusion (IR) injury, and other factors.1-3 Although this approach is commonly used in clinical practice, it provides a relatively late prediction of the patient's response to these drugs and can potentially lead to a prolonged period of suboptimal levels of a given immunosuppressant in the postoperative period, posing an increased risk for rejection. The ability to assess and predict graft metabolic function could be beneficial in determining appropriate individual immunosuppressant dosing in the posttransplant period. Because of the continuing shortage of suitable cadaveric donor livers for the ever-growing number of pa-

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“…Tacrolimus is effective in preventing graft rejection2; however, it has a narrow therapeutic range and requires close monitoring to ensure that both supra‐ and subtherapeutic concentrations are avoided 1, 2. Trough concentrations below the therapeutic range are associated with increased risk of rejection,3, 4, 5 whereas blood concentrations above the therapeutic range increase the risk of toxicity 6, 7, 8…”

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confidence: 99%

Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended‐Release Once‐Daily Tacrolimus Tablets

Philosophe

Leca

West-Thielke

et al. 2018

The Journal of Clinical Pharma

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The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice‐daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once‐daily tacrolimus formulations such as LCPT (an extended‐release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once‐daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24‐hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24‐hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24‐hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation.

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Clinical Utility of Monitoring Tacrolimus Blood Concentrations in Liver Transplant Patients

Cited by 147 publications

References 20 publications

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients

Predicting immunosuppressant dosing in the early postoperative period with noninvasive indocyanine green elimination following orthotopic liver transplantation

Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended‐Release Once‐Daily Tacrolimus Tablets

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