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Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study.

Bremer S, Vethe NT, Rootwelt H, Jørgensen PF, Stenstrøm J, Holdaas H, Midtvedt K, Bergan S - J Transl Med (2009)

Bottom Line: The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6).One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression.The significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway. sara.bremer@rikshospitalet.no

ABSTRACT

Background: Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2nd generation CTLA4-Ig) or cyclosporine (CsA).

Methods: Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two IMPDH isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.

Results: The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC0-9 h and C0) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for IMPDH1 expression, starting at week 1. Higher MPA exposure was associated with larger elevations of IMPDH1 (r = 0.81, P = 0.023, n = 7 for MPA and IMPDH1 AUC0-9 h at week 1). The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression. No difference was observed in T cell subsets between treatment groups.

Conclusion: The significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.

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Median gene expressions of IMPDH1 and IMPDH2 (% of predose) among renal allograft recipients. The vertical lines correspond to the range of total observations. Profiles of patients in the belatacept group (n = 3) at weeks 1, 2 and 13 (A, B and C) and the cyclosporine group (n = 3) at weeks 1, 2 and 13 (D, E and F).
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Figure 3: Median gene expressions of IMPDH1 and IMPDH2 (% of predose) among renal allograft recipients. The vertical lines correspond to the range of total observations. Profiles of patients in the belatacept group (n = 3) at weeks 1, 2 and 13 (A, B and C) and the cyclosporine group (n = 3) at weeks 1, 2 and 13 (D, E and F).

Mentions: The 9 hour-profiles showed rapid changes of IMPDH1 expression postdose, while IMPDH2 expression was relatively stable (Figure 3). At week 1, IMPDH1 expression was transiently upregulated for belatacept patients, while CsA patients displayed downregulation. With longer time on immunosuppressive therapy, including higher MPA exposure, increasing transient inductions of IMPDH1 expression were observed postdose for both treatment groups (Table 3). At week 13, the maximum expression (Emax, % of E0) of IMPDH1 was 52 (13–177)% higher than at week 1 (n = 6, P = 0.031). A similar trend was observed for IMPDH1 AUC0–9 h expression (n = 6, P = 0.094). Compared to healthy controls (n = 5), the patients (n = 6) demonstrated higher IMDPH1 Emax at week 13 (P = 0.004), being 101 (100–116)% and 167 (118–193)%, respectively. Considering IMPDH1 AUC0–6 hexpression, CsA patients (n = 3) displayed higher levels at week 13 than controls (P = 0.036). Among belatacept patients (n = 3), IMPDH1 AUC0–6 h expression was elevated at week 1 (P = 0.032) and tended to be increased at week 13 (P = 0.071), compared to healthy controls (Additional file 1: IMPDH activity and IMPDH1 expression in patients on MMF therapy compared to healthy individuals). One of the patients with MMF dose reduction experienced lower MPA exposure with time, and did neither display elevations of IMPDH activity nor IMPDH1 expression (Figure 2). The first week posttransplant, IMPDH1 AUC0–9 h expression correlated with MPA C0 (r = 0.76, P = 0.047, n = 7) and MPA AUC0–9 h (r = 0.81, P = 0.027, n = 7). An association was also observed between minimum IMPDH1 expression (Emin) and MPA AUC0–9 h (r = 0.82, P = 0.023, n = 7). This implies that higher MPA exposure is associated with larger increases of IMPDH1 expression postdose.


Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study.

Bremer S, Vethe NT, Rootwelt H, Jørgensen PF, Stenstrøm J, Holdaas H, Midtvedt K, Bergan S - J Transl Med (2009)

Median gene expressions of IMPDH1 and IMPDH2 (% of predose) among renal allograft recipients. The vertical lines correspond to the range of total observations. Profiles of patients in the belatacept group (n = 3) at weeks 1, 2 and 13 (A, B and C) and the cyclosporine group (n = 3) at weeks 1, 2 and 13 (D, E and F).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724496&req=5

Figure 3: Median gene expressions of IMPDH1 and IMPDH2 (% of predose) among renal allograft recipients. The vertical lines correspond to the range of total observations. Profiles of patients in the belatacept group (n = 3) at weeks 1, 2 and 13 (A, B and C) and the cyclosporine group (n = 3) at weeks 1, 2 and 13 (D, E and F).
Mentions: The 9 hour-profiles showed rapid changes of IMPDH1 expression postdose, while IMPDH2 expression was relatively stable (Figure 3). At week 1, IMPDH1 expression was transiently upregulated for belatacept patients, while CsA patients displayed downregulation. With longer time on immunosuppressive therapy, including higher MPA exposure, increasing transient inductions of IMPDH1 expression were observed postdose for both treatment groups (Table 3). At week 13, the maximum expression (Emax, % of E0) of IMPDH1 was 52 (13–177)% higher than at week 1 (n = 6, P = 0.031). A similar trend was observed for IMPDH1 AUC0–9 h expression (n = 6, P = 0.094). Compared to healthy controls (n = 5), the patients (n = 6) demonstrated higher IMDPH1 Emax at week 13 (P = 0.004), being 101 (100–116)% and 167 (118–193)%, respectively. Considering IMPDH1 AUC0–6 hexpression, CsA patients (n = 3) displayed higher levels at week 13 than controls (P = 0.036). Among belatacept patients (n = 3), IMPDH1 AUC0–6 h expression was elevated at week 1 (P = 0.032) and tended to be increased at week 13 (P = 0.071), compared to healthy controls (Additional file 1: IMPDH activity and IMPDH1 expression in patients on MMF therapy compared to healthy individuals). One of the patients with MMF dose reduction experienced lower MPA exposure with time, and did neither display elevations of IMPDH activity nor IMPDH1 expression (Figure 2). The first week posttransplant, IMPDH1 AUC0–9 h expression correlated with MPA C0 (r = 0.76, P = 0.047, n = 7) and MPA AUC0–9 h (r = 0.81, P = 0.027, n = 7). An association was also observed between minimum IMPDH1 expression (Emin) and MPA AUC0–9 h (r = 0.82, P = 0.023, n = 7). This implies that higher MPA exposure is associated with larger increases of IMPDH1 expression postdose.

Bottom Line: The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6).One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression.The significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, Norway. sara.bremer@rikshospitalet.no

ABSTRACT

Background: Mycophenolic acid (MPA) is widely used as part of immunosuppressive regimens following allograft transplantation. The large pharmacokinetic (PK) and pharmacodynamic (PD) variability and narrow therapeutic range of MPA provide a potential for therapeutic drug monitoring. The objective of this pilot study was to investigate the MPA PK and PD relation in combination with belatacept (2nd generation CTLA4-Ig) or cyclosporine (CsA).

Methods: Seven renal allograft recipients were randomized to either belatacept (n = 4) or cyclosporine (n = 3) based immunosuppression. Samples for MPA PK and PD evaluations were collected predose and at 1, 2 and 13 weeks posttransplant. Plasma concentrations of MPA were determined by HPLC-UV. Activity of inosine monophosphate dehydrogenase (IMPDH) and the expressions of two IMPDH isoforms were measured in CD4+ cells by HPLC-UV and real-time reverse-transcription PCR, respectively. Subsets of T cells were characterized by flow cytometry.

Results: The MPA exposure tended to be higher among belatacept patients than in CsA patients at week 1 (P = 0.057). Further, MPA concentrations (AUC0-9 h and C0) increased with time in both groups and were higher at week 13 than at week 2 (P = 0.031, n = 6). In contrast to the postdose reductions of IMPDH activity observed early posttransplant, IMPDH activity within both treatment groups was elevated throughout the dosing interval at week 13. Transient postdose increments were also observed for IMPDH1 expression, starting at week 1. Higher MPA exposure was associated with larger elevations of IMPDH1 (r = 0.81, P = 0.023, n = 7 for MPA and IMPDH1 AUC0-9 h at week 1). The maximum IMPDH1 expression was 52 (13-177)% higher at week 13 compared to week 1 (P = 0.031, n = 6). One patient showed lower MPA exposure with time and did neither display elevations of IMPDH activity nor IMPDH1 expression. No difference was observed in T cell subsets between treatment groups.

Conclusion: The significant influence of MPA on IMPDH1 expression, possibly mediated through reduced guanine nucleotide levels, could explain the elevations of IMPDH activity within dosing intervals at week 13. The present regulation of IMPDH in CD4+ cells should be considered when interpreting measurements of IMPDH inhibition.

Show MeSH
Related in: MedlinePlus