Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients

Abstract

Aims: Pharmacokinetic (PK) and pharmacodynamic (PD) monitoring strategies and clinical outcome were evaluated in enteric-coated mycophenolate sodium (EC-MPS)-treated renal allograft recipients.

Methods: PK [mycophenolic acid (MPA)] and PD [inosine monophosphate dehydrogenase (IMPDH) activity] data were analysed in 66 EC-MPS and ciclosporin A (CsA)-treated renal allograft recipients. Adverse events were considered in a follow-up period of 12 weeks.

Results: Analyses confirmed a limited sampling strategy (LSS) consisting of PK and PD data at predose, 1, 2, 3 and 4 h after oral intake as an appropriate sampling method (MPA r(2)= 0.812; IMPDH r(2)= 0.833). MPA AUC(0-12) of patients with early biopsy-proven acute rejection was significantly lower compared with patients without a rejection (median MPA AUC(0-12) 28 microg*h ml(-1) (7-45) vs. 40 microg*h ml(-1) (16-130), P < 0.01), MPA AUC(0-12) of patients with recurrent infections was significantly higher compared with patients without infections (median MPA AUC(0-12) 65 microg*h ml(-1) (range 37-130) vs. 37 microg*h ml(-1) (range 7-120), P < 0.005). Low 12-h IMPDH enzyme activity curve (AEC(0-12)) was associated with an increased frequency of gastrointestinal side-effects (median IMPDH AEC(0-12) 43 nmol*h mg(-1) protein h(-1)[range 12-67) vs. 75 nmol*h mg(-1) protein h(-1) (range 15-371), P < 0.01].

Conclusions: Despite highly variable absorption data, an appropriate LSS might be estimated by MPA AUC(0-4) and IMPDH AEC(0-4) in renal transplant patients treated with EC-MPS and CsA. Regarding adverse events, the suggested MPA-target AUC(0-12) from 30 to 60 microg*h ml(-1) seems to be appropriate in renal allograft recipients.

Figures

Figure 3

Median time profiles of plasma mycophenolic acid (MPA) concentration and inosine monophosphate dehydrogenase (IMPDH) activity in peripheral mononuclear cells of 66 renal transplant patients on enteric-coated mycophenolate sodium (EC-MPS) therapy are presented (median, 25 and 75 percentile; solid line, MPA concentration; dashed line, IMPDH activity). MPA concentration [µg ml−1] (); IMPDH activity [nmol/mg protein/h] ()

Figure 2

Assessment of pharmacodynamic response by plotting inosine monophosphate dehydrogenase (IMPDH) activity against plasma mycophenolic acid (MPA) concentration

Figure 1

Association of MPA AUC0–12 and IMPDH AEC0–12 is demonstrated. AUC, area under the concentration–time curve; AEC, area under the enzyme activity curve; IMPDH, inosine monophosphate dehydrogenase; MPA, mycophenolic acid

Figure 4

Box and whisker plot shows the median, interquartile range, outliers (°) and extreme values (*) of the evaluated abbreviated sampling strategy MPA AUC0–4 in patients (a) with and without acute rejection episode (P < 0.05), (b) with and without recurrent infections (P < 0.05), and with and without gastrointestinal side-effects (NS). AUC, area under the concentration–time curve; MPA, mycophenolic acid

Figure 5

Box and whisker plot shows the median, interquartile range, outliers (°) and extreme values (*) of the evaluated abbreviated sampling strategy IMPDH AEC0–4 in patients (a) with and without acute rejection episode (NS), (b) with and without recurrent infections (NS), and (c) with and without gastrointestinal side-effects (P < 0.05). AEC, area under the enzyme activity curve; IMPDH, inosine monophosphate dehydrogenase