How common is delayed cyclosporine absorption following liver transplantation?

Yantorno, Silvina; Varela, E B; Raffa, S.; Descalzi, Valeria; Carretero, Maria L. Gomez; Pirola, Daniel A.; Ruf, Andrés E.; Carabuz, G I Martinez; Podestá, Luis G.; Villamil, Federico

doi:10.1002/lt.20341

Cited by 10 publications

(9 citation statements)

References 13 publications

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“…Guidance of use of C 2 monitoring based on the experience from this study has been recently published, 9 as well as further data on delayed absorption. 10 An increase in patient and graft survival was observed at 6 months and maintained at 12 months among HCV-positive patients from the CsA-ME group compared to the tacrolimus group, whereas no such difference in death or graft loss was seen in non-HCV transplanted patients. The 2 cohorts were comparable at baseline.…”

Section: Discussionmentioning

confidence: 81%

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

Levy¹,

Grazi²,

Mühlbacher³

et al. 2006

Liver Transpl

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The LIS2T study was an open-label, multicenter study in which recipients of a primary liver transplant were randomized to cyclosporine microemulsion (CsA-ME) (Neoral) (n ϭ 250) (monitoring of blood concentration at 2 hours postdose) C 2 or tacrolimus (n ϭ 245) (monitoring of trough drug blood level [predose]) C 0 to compare efficacy and safety at 3 and 6 months and to evaluate patient status at 12 months. All patients received steroids with or without azathioprine. At 12 months, 85% of CsA-ME patients and 86% of tacrolimus patients survived with a functioning graft (P not significant). Efficacy was similar in deceased-and living-donor recipients. Significantly fewer hepatitis C-positive patients died or lost their graft by 12 months with CsA-ME (5/88, 6%) than with tacrolimus (14/85, 16%) (P Ͻ 0.03). Recurrence of hepatitis C virus in liver grafts was similar in each group. Based on biopsies driven by clinical events, the mean time to histological diagnosis of hepatitis C virus recurrence was significantly longer with CsA-ME (100 Ϯ 50 days) than with tacrolimus (70 Ϯ 40 days) (P Ͻ 0.05). Median serum creatinine at 12 months was 106 mol/L with CsA-ME and with tacrolimus. More patients who were nondiabetic at baseline received antihyperglycemic therapy in the tacrolimus group at 12 months (13% vs. 5%, P Ͻ 0.01). Of patients who were diabetic at baseline, more tacrolimus-treated individuals required anti-diabetic treatment at 12 months (70% vs. 49%, P ϭ 0.02). Treatment for de novo or preexisting hypertension or hyperlipidemia was similar in both groups. In conclusion, the efficacy of CsA-ME monitored by blood concentration at 2 hours postdose and tacrolimus in liver transplant patients is equivalent to 12 months, and renal function is similar. More patients required antidiabetic therapy with tacrolimus regardless of diabetic status at baseline. Abbreviations: CsA-ME, cyclosporine microemulsion; CsA, cyclosporine; C 2, blood concentration at 2 hours postdose; HCV, hepatitis C virus; C 0, trough drug blood level (predose).

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Section: Discussionmentioning

confidence: 81%

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

Levy¹,

Grazi²,

Mühlbacher³

et al. 2006

Liver Transpl

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“…Cyclosporine has been orally administered in 2 divided doses every 12 hours in transplant patients. However, some patients have difficulty in achieving therapeutic C 2 levels early after liver transplantation because of delayed and/or poor absorption,9 probably caused by postoperative paralytic ileus and external biliary drainage. Furthermore, C 0 levels are frequently elevated by a continuous dose escalation as well as by the decreased metabolic function in the grafted liver within the early postoperative period.…”

mentioning

confidence: 99%

Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosing

Fukudo¹,

Yano²,

Masuda³

et al. 2006

Liver Transpl

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We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once-and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n ϭ 5) or once daily in the morning (QD, n ϭ 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C 2 ) and area under the concentration-time curve (AUC) for 4 hours (AUC 0 -4 ), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA 0 -12 ) and 24 hours (AUA 0 -24 ) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C 2 level was significantly correlated with the AUC 0 -4 (r 2 ϭ 0.95), which was negatively related to the AUA 0 -12 with a large interindividual variability (r 2 ϭ 0.59). However, a significant correlation was found between the AUA 0 -12 or AUA 0 -24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (E max ) model, the mean estimates of E max and the C b value that gives a half-maximal effect (EC 50 ) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Living-donor liver transplantation (LDLT) is now acknowledged as a lifesaving therapy for patients with end-stage liver failure. Cyclosporine is a calcineurin (CaN) inhibitor that has been widely used to prevent acute rejections after liver transplantation. 1 Cyclosporine has a narrow therapeutic range and shows large inter-and intraindividual pharmacokinetic variability. Therefore, therapeutic drug monitoring of trough blood concentrations (C 0 ) has been required to avoid adverse events such as nephrotoxicity and neurotoxicity. 2 However, the C 0 level does not correlate well with the systemic drug exposure and clinical outcomes. 3,4 Since a microemulsion formulation of cyclosporine (Neoral) has been introduced into organ transplantation, a consisAbbreviations: LDLT, living-donor liver transplantation; BID, twice a day; QD, once a day; POD, postoperative day; C b , blood concentration; C 0 , trough blood concentration; C 2 , blood concentration at 2 hours postdose; CaN, calcineurin; AUC, area under the concentration-time curve; AUA, area under the CaN activity-time curve; PBMC, peripheral blood mononuclear cell; E max , maximum inhibitory effect attributable to the drug; EC 50 C b , value that gives a half-maximal effect.

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“…A second analysis of the data was performed excluding patients who switched therapy, and the results of this analysis did not differ from the intent to treat analysis. Guidance of use of C 2 monitoring based on the experience from this study has been recently published,9 as well as further data on delayed absorption 10…”

Section: Discussionmentioning

confidence: 96%

Impact of the Merrifield solid phase method on the design and synthesis of selective agonists and antagonists of oxytocin and vasopressin: A historical perspective

Manning

2008

Biopolymers

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This tribute to Bruce Merrifield traces the author's fortuitous path in 1964 from Vincent du Vigneaud's laboratory to the laboratory of D. W. Woolley to learn the solid phase method and then to his first faculty position in the Department of Biochemistry, McGill University, Montreal in 1965. It recalls the key roles played from early 1966 to July 1967 by Bruce Merrifield, John Stewart, Arnold Marglin, Herb Takashima, and Vincent du Vigneaud in providing key advice to the author's efforts to use the solid phase method to synthesize oxytocin; while simultaneously the du Vigneaud and Merrifield laboratories were collaborating on the solid phase synthesis of deamino‐oxytocin. Both syntheses were published in the same issue of the Journal of American Chemical Society in 1968. Also described is how this breakthrough impacted the author's scientific career: by leading to highly productive collaborative studies, initially with Wilbur H. Sawyer and subsequently with others, on the design and synthesis of selective agonists, antagonists, and radioiodinated ligands for oxytocin and vasopressin receptors. These syntheses were greatly facilitated by the contributions of highly talented graduate students, research technicians, and visiting peptide chemists from Hungary, England, Poland, Bulgaria, and China. Many of these peptides have become very valuable pharmacological tools in studies on the peripheral and central effects of oxytocin and vasopressin: further attesting to the profound impact of the solid phase method as the cornerstone for all the discoveries, which he and his collaborators and coworkers have made over the past 40 years. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 203–212, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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How common is delayed cyclosporine absorption following liver transplantation?

Cited by 10 publications

References 13 publications

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus

Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosing

Impact of the Merrifield solid phase method on the design and synthesis of selective agonists and antagonists of oxytocin and vasopressin: A historical perspective

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