Time-dependent clearance of mycophenolic acid in renal transplant recipients

Abstract

Aims: Pharmacokinetic studies of the immunosuppressive compound mycophenolic acid (MPA) have shown a structural decrease in clearance (CL) over time after renal transplantation. The aim of this study was to characterize the time-dependent CL of MPA by means of a population pharmacokinetic meta-analysis, and to test whether it can be described by covariate effects.

Methods: One thousand eight hundred and ninety-four MPA concentration-time profiles from 468 renal transplant patients (range 1-9 profiles per patient) were analyzed retrospectively by nonlinear mixed effect modelling. Sampling occasions ranged from day 1-10 years after transplantation.

Results: The pharmacokinetics of MPA were described by a two-compartment model with time-lagged first order absorption, and a first-order term for time-dependent CL. The model predicted the mean CL to decrease from 35 l h(-1) (CV = 44%) in the first week after transplantation to 17 l h(-1) (CV = 38%) after 6 months. In a covariate model without a term for time-dependent CL, changes during the first 6 months after transplantation in creatinine clearance from 19 to 71 ml min(-1), in albumin concentration from 35 to 40 g l(-1), in haemoglobin from 9.7 to 12 g dl(-1) and in cyclosporin predose concentration from 225 to 100 ng ml(-1) corresponded with a decrease of CL from 32 to 19 l h(-1). Creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration explained, respectively, 19%, 12%, 4% and 3% of the within-patient variability in MPA CL.

Conclusions: By monitoring creatinine clearance, albumin concentration, haemoglobin and cyclosporin predose concentration, changes in MPA exposure over time can be predicted. Such information can be used to optimize therapy with mycophenolate mofetil.

Figure 1

a) Time after renal transplantation vs. mycophenolic acid (MPA) clearance (CL) based on the basic model with time-dependent CL. Open circles are individual Bayesian estimated CL values, and the solid line represents the model estimated relationship between time and CL according to equation 7. b) Time after renal transplantation vs. MPA CL based on the final model. Open circles are Bayesian estimated CL values and the solid line represents the median MPA CL–time course

Figure 2

a) Correlation between creatinine clearance (CL_CR) and mycophenolic acid (MPA) clearance (CL) as identified in the final model. The solid line represents the model predicted relationship for a typical patient with an albumin concentration of 38 g l⁻¹, a haemoglobin of 11 g dl⁻¹ and a cyclosporin predose concentration of 200 ng ml⁻¹ according to equation 8. b) Correlation between albumin concentration and MPA CL as identified in the final model. The solid line represents the model predicted relationship for a typical patient with a CL_CR of 50 ml min⁻¹, a haemoglobin of 11 g dl⁻¹ and a cyclosporin predose concentration of 200 ng ml⁻¹ according to equation 8. The broken lines in both (a) and (b) represent the 5 and 95%iles of the between-patient variability in both relationships, illustrating that the magnitude of the effect of CL_CR and albumin concentration on MPA CL varies between individuals. Thus a given change in CL_CR or albumin concentration can have a large effect on MPA CL in one patient (95%ile, dotted line), but a small effect in another patient (5%ile, dashed line). The between-patient variability in the effects of CL_CR and albumin concentration on MPA CL was modelled according equation 6. Because CL_CR values above 120 ml min⁻¹ are not physiologically plausible in renal transplant patients, the solid and broken lines in (a) are truncated at 120 ml min⁻¹. Data for CL_CR above 150 ml min⁻¹ are not shown (n = 4)

Figure 3

Goodness-of-fit plots for the final model. a) Population predicted mycophenolic acid (MPA) concentration vs. observed MPA concentration, b) Individual Bayesian predicted MPA concentration vs. observed MPA concentration, c) Protocol sample time vs. weighed residuals and d) population predicted MPA concentration vs. weighed residuals. The solid lines in (a) and (b) represent the lines of identity. The dotted lines in (c) and (d) represents the line y = 0. The small solid horizontal lines in (c) represent the median weighed residual for the protocol sampling times