Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation

Abstract

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 microg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 microg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 microg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 microg/mL could prevent graft rejection.

Figure 1.

Mycophenolic acid plasma concentration steady state (MPA Css) on days 7 and 21 after HCT. The twice-daily MMF group is represented by squares and 3-times-daily MMF group by circles.

Figure 2.

Correlation between MPA Ctrough and total MPA Css. The twice-daily MMF group is represented by squares and 3-times-daily MMF group by circles. (A) MPA assessments on day 7. Seventy-five patients are represented (r = 0.57; P < .001). (B) MPA assessments on day 21. Seventy-five patients are represented (r = 0.70; P < .001). The values off the x-axis scale are shown in the dotted line box.

Figure 3.

Correlation between total MPA Css and unbound MPA Css. The twice-daily MMF group is represented by squares and 3-times-daily MMF group by circles. A total of 75 patients (35 from twice-daily MMF group and 40 from 3-times-daily MMF group) and 123 MPA assessments are represented.

Figure 4.

Correlation between the degree of CD3⁺ donor chimerism and MPA Css. Data from the day-7 and day-21 MPA Css evaluation and day 28, 56, 84 chimerism analyses are shown (6 recipients of bone marrow were excluded). The twice-daily MMF group is represented by squares and the 3-times-daily MMF group by circles. (A) Total MPA Css, 79 patients (P = .04). (B) Unbound MPA Css, 70 patients (P = .02).