The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

Gustafsson, Finn; Barth, David; Delgado, Diego; Nsouli, Meerna; Sheedy, Jill; Ross, Heather J.

doi:10.1007/s00228-009-0663-2

Cited by 3 publications

(6 citation statements)

References 21 publications

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“…Contradictory findings have been reported for CsA. A study by Gustafsson et al [125] involving heart transplant recipients co-treated with MPA reported a high correlation (r 2 = 0.98, p < 0.001) between CsA concentrations in 2 h postdose (C 2 ) whole blood samples and lymphocyte AUC 0–12h exposure (expressed as ng × h/10– 6 cells). In contrast, a poor correlation was reported in patients co-treated with EVE (r 2 = 0.24, p = 0.18).…”

Section: Intracellular Concentrationmentioning

confidence: 96%

Alternative Matrices for Therapeutic Drug Monitoring of Immunosuppressive Agents Using LC–MS/MS

Ghareeb

Akhlaghi

2015

Bioanalysis

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Immunosuppressive drugs used in solid organ transplants typically have narrow therapeutic windows and high intra- and intersubject variability. To ensure satisfactory exposure, therapeutic drug monitoring (TDM) plays a pivotal role in any successful posttransplant maintenance therapy. Currently, recommendations for optimum immunosuppressant concentrations are based on blood/plasma measurements. However, they introduce many disadvantages, including poor prediction of allograft survival and toxicity, a weak correlation with drug concentrations at the site of action and the invasive nature of the sample collection. Thus, alternative matrices have been investigated. This paper reviews tandem-mass spectrometry (LC–MS/MS) methods used for the quantification of immunosuppressant drugs utilizing nonconventional matrices, namely oral fluids, fingerprick blood and intracellular and intratissue sampling. The advantages, disadvantages and clinical application of such alternative mediums are discussed. Additionally, sample extraction techniques and basic chromatography information regarding these methods are presented in tabulated form.

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Section: Intracellular Concentrationmentioning

confidence: 96%

Alternative Matrices for Therapeutic Drug Monitoring of Immunosuppressive Agents Using LC–MS/MS

Ghareeb

Akhlaghi

2015

Bioanalysis

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“…Concerns that serum cyclosporine levels may not accurately reflect overall tissue cyclosporine exposure when given with concomitant everolimus have been raised [22]. The potential for primary nephrotoxicity from PSIs requires further study.…”

Section: Expert Opinionmentioning

confidence: 98%

“…PSIs that are also substrates for g-glycoprotein increase kidney tissue CsA concentrations when given in combination, possibly potentiating renal toxicity [21]. As opposed to MMF treated patients (where correlation is excellent), CsA tissue exposure has a poor correlation to CsA trough (C0) and 2 h (C2) measurements when co-administered with everolimus [22].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Renal failure Direct renal toxicity remains controversial Potentiates CNI toxicity potentially by increasing tissue exposure without increasing blood levels [20][21][22] Dose reduction of CNI by~40% [27] Proteinuria Ranges from tubular to glomerular range proteinuria Pathological changes to podocyte morphology Presence of proteinuria predictive of attenuated renal recovery with CNI reduction strategies [67] Reduction of proteinuria with treatment with renin-angiotensin-antagonist Edema Unilateral or bilateral upper/lower extremity peripheral edema Facial/eyelid edema [80] Less frequent in everolimus vs sirolimus [81] Reduce or eliminate PSI dose Avoid concomitant use of calcium channel blockers with exacerbate edema Pericardial effusions Early and late cases seen in PSI treated patients. Probably lower in everolimus compared to sirolimus Routine echocardiography following initiation of PSI Thrombocytopenia Dose related thrombocytopenia [54] Usually resolves with dose reduction [54] …”

Section: Adverse Event Findings Therapymentioning

confidence: 99%

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Everolimus: efficacy and safety in cardiac transplantation

Schaffer

Ross

2010

Expert Opinion on Drug Safety

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“…However, since CsA exerts its immunosuppressive effect within T-lymphocytes [6], measurement of CsA within these cells may provide more relevant information regarding the immunosuppressive effect of CsA than whole blood concentrations. Several groups have shown data that support this hypothesis in transplant recipients [5,7-10]. We have recently shown that intracellular CsA concentration in T-lymphocytes decreased several days before an acute rejection was possible to diagnose in renal transplants by current standard clinical methods [7].…”

Section: Introductionmentioning

confidence: 95%

Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients

et al. 2013

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BackgroundIn the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections. Previous studies indicate that intracellular ciclosporin A (CsA) concentration may be a sensitive acute rejection marker in renal transplant recipients. The aims of this study were to evaluate the relationships between CsA concentrations at different target sites as potential therapeutic drug monitoring (TDM) tools in heart transplant recipients.MethodsTen heart transplant recipients (8 men, 2 women) on CsA-based immunosuppression were enrolled in this prospective single-center pilot study. Blood samples were obtained once to twice weekly up to 12 weeks post-transplant. One of the routine biopsies was allocated to this study at each sampling time. Whole blood, intralymphocyte, and endomyocardial CsA concentrations were determined with validated HPLC-MS/MS-methods. Mann–Whitney U test was used when evaluating parameters between the two groups of patients. To correlate whole blood, intralymphocyte, and endomyocardial CsA concentrations linear regression analysis was used.ResultsThree patients experienced mild rejections. In the study period, the mean (range) intralymphocyte CsA trough concentrations were 10.1 (1.5 to 39) and 8.1 (1.3 to 25) ng/106 cells in the rejection and no-rejection group, respectively (P=0.21). Corresponding whole blood CsA concentrations were 316 (153 to 564) and 301 (152 to 513) ng/mL (P=0.33). There were no correlations between whole blood, intralymphocyte, or endomyocardial concentrations of CsA (P >0.11).ConclusionsThe study did not support an association between decreasing intralymphocyte CsA concentrations and acute rejections. Further, there were no association between blood concentrations and concentrations at sites of action, potentially challenging TDM in these patients.

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The impact of everolimus versus mycophenolate on blood and lymphocyte cyclosporine exposure in heart-transplant recipients

Abstract: Standard blood CsA levels accurately predict intralymphocytic exposure to CsA in patients concomitantly treated with MMF but not in patients treated with everolimus.

Cited by 3 publications

References 21 publications

Alternative Matrices for Therapeutic Drug Monitoring of Immunosuppressive Agents Using LC–MS/MS

Alternative Matrices for Therapeutic Drug Monitoring of Immunosuppressive Agents Using LC–MS/MS

Everolimus: efficacy and safety in cardiac transplantation

Endomyocardial, intralymphocyte, and whole blood concentrations of ciclosporin A in heart transplant recipients

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