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

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.

Figure 1

Median inosine monophosphate dehydrogenase (IMPDH) activity (% of predose) and mycophenolic acid (MPA) concentrations among renal allograft recipients. The vertical lines represent 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). (Observe scale on right y-axis of C.)

Figure 2

Individual 0–9 hours area under the curve (AUC) for 6 renal transplant patients at week 13 compared to week 1. Solid lines denote belatacept patients (n = 3) while broken lines represent CsA patients (n = 3). Data are provided for A: mycophenolic acid (MPA) AUC_{0–9 h}, B: inosine monophosphate dehydrogenase (IMPDH) activity AUC_{0–9 h} and C: IMPDH1 expression AUC_{0–9 h}.

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).