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

Robertsen I, Falck P, Andreassen AK, Næss NK, Lunder N, Christensen H, Gullestad L, Asberg A - Transplant Res (2013)

Bottom Line: In the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections.The 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P,O, Box 1068, Blindern, Oslo, 0316, Norway. ida.robertsen@farmasi.uio.no.

ABSTRACT

Background: In 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.

Methods: Ten 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.

Results: Three 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).

Conclusions: The 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.

No MeSH data available.


Related in: MedlinePlus

Ratio between the mean concentration of the metabolites AM19, AM1c9, AM1, AM9, AM1c, and AM4N in patients with CYP3A5*1/3 and in patients with CYP3A5*3/*3.
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Figure 3: Ratio between the mean concentration of the metabolites AM19, AM1c9, AM1, AM9, AM1c, and AM4N in patients with CYP3A5*1/3 and in patients with CYP3A5*3/*3.

Mentions: Genotyping results for both ABCB1 (1199G>A, 1236C>T, 2677G>T, 2677G>A, 2677G>G, and 3435G>T) and CYP3A5 (*3) are presented in Table 2. Two out of three patients in the rejection group were homozygote ABCB1 TTT carriers, but all patients were potential carriers of this reduced P-gp function haplotype. Three of the 10 patients expressed functional CYP3A5 enzymes (CYP3A5*1), one in the rejection group. It was observed that the patients expressing functional CYP3A5 enzymes tended to have higher concentrations of the metabolites AM19 (P=0.21), AM1c9 (P=0.57), AM1c (P=0.73), AM4N (P=0.27), similar concentration of AM9 (P=0.43), and a decreased concentration of AM1 (P=0.57) compared to the patients without functional CYP3A5 (Figure 3). We did not observe a significant difference in renal function between patients expressing functional CYP3A5 (eGFR of 51 ±23 mL/min) and patients not expressing functional CYP3A5 (eGFR of 66 ±19 mL/min, P=0.38). One of the three patients expressing functional CYP3A5 experienced renal failure during the study period.


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

Robertsen I, Falck P, Andreassen AK, Næss NK, Lunder N, Christensen H, Gullestad L, Asberg A - Transplant Res (2013)

Ratio between the mean concentration of the metabolites AM19, AM1c9, AM1, AM9, AM1c, and AM4N in patients with CYP3A5*1/3 and in patients with CYP3A5*3/*3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643826&req=5

Figure 3: Ratio between the mean concentration of the metabolites AM19, AM1c9, AM1, AM9, AM1c, and AM4N in patients with CYP3A5*1/3 and in patients with CYP3A5*3/*3.
Mentions: Genotyping results for both ABCB1 (1199G>A, 1236C>T, 2677G>T, 2677G>A, 2677G>G, and 3435G>T) and CYP3A5 (*3) are presented in Table 2. Two out of three patients in the rejection group were homozygote ABCB1 TTT carriers, but all patients were potential carriers of this reduced P-gp function haplotype. Three of the 10 patients expressed functional CYP3A5 enzymes (CYP3A5*1), one in the rejection group. It was observed that the patients expressing functional CYP3A5 enzymes tended to have higher concentrations of the metabolites AM19 (P=0.21), AM1c9 (P=0.57), AM1c (P=0.73), AM4N (P=0.27), similar concentration of AM9 (P=0.43), and a decreased concentration of AM1 (P=0.57) compared to the patients without functional CYP3A5 (Figure 3). We did not observe a significant difference in renal function between patients expressing functional CYP3A5 (eGFR of 51 ±23 mL/min) and patients not expressing functional CYP3A5 (eGFR of 66 ±19 mL/min, P=0.38). One of the three patients expressing functional CYP3A5 experienced renal failure during the study period.

Bottom Line: In the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections.The 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, P,O, Box 1068, Blindern, Oslo, 0316, Norway. ida.robertsen@farmasi.uio.no.

ABSTRACT

Background: In 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.

Methods: Ten 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.

Results: Three 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).

Conclusions: The 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.

No MeSH data available.


Related in: MedlinePlus