We observed significant inter-individual variability in both pharmacokinetics and pharmacodynamics of mycophenolic acid. Additionally, we present initial evidence that personalized cSLE disease control may be related to sufficient exposure to MMF. Both statements support the notion that personalized MMF regimens, based on MPA-PK and/or MPA-PD, may be preferable to the current weight-based approach of MMF dosing in cSLE patients.
Weight-adjusted MMF dosing only moderately correlated with patients’ actual exposure to the biologically active drug. Our data support that MPA exposure, as quantified by AUC0-12
, is related to maximum IMPDH inhibition, supporting the usefulness of IMPDH as a PD target. To date, IMPDH activity is not routinely assessed in transplant patients and, to the best of our knowledge, has not been studied in cSLE. Although these findings certainly warrant larger studies, we are encouraged as our results are consistent with what is currently known about both MPA-PK and MPA-PD in the field of solid organ transplantation (24
). If confirmed, IMPDH activity may serve as a biomarker of MPA-PD which may be of significant utility in determining the starting dose of MMF. Given the close relationship of MPA-PK and MPA-PD, MMF dose adjustments based on MPA-PK appear justified during maintenance therapy.
We found weight-based MMF dosing to be only moderately related to exposure to the biologically active MPA. Thus, in contrast to other commonly used anti-inflammatory medications, weight-based MMF dosing does not appear to be useful in estimating the adequacy of MPA exposure in patients with cSLE. Our findings are in line with prior studies in transplant patients and patients with adulthood-onset of SLE which show similar large inter-individual variability in MPA PK (32
We also present initial evidence that disease activity change over time is related to MPA exposure. Although this finding can only be considered as preliminary given the exploratory nature of our study, an MPA AUC0-12
level of 30 mg*h/L or higher was associated with improved disease control of cSLE, whereas MPA AUC0-12
levels lower than that were not. This tentative AUC0-12
target of >30 mg*h/L coincides with the recommended lower MPA AUC0-12
target in transplant recipients (24
) and is consistent with reports by Zahr et al in adult SLE (40
Due to its general ability to induce uridine diphosphate glucuronosyltransferase (UGT) (42
), which is responsible for MPA metabolism, corticosteroids have been proposed to decrease MPA clearance and therefore increase MPA exposure (18
). To date, corticosteroid interaction with the specific UGTs involved in MPA metabolism has not been extensively studied (45
), and renal transplant studies have concluded that corticosteroids do not influence MPA-PK (45
). In this study, we did not find a relevant correlation between the prednisone dose and MPA AUC0-12
, despite a wide range in prednisone dosing (data not shown). Inter-individual differences in the PK profiles of patients treated with MMF are also likely influenced to an extent by genetic polymorphisms involving the enzymes responsible for transporter-facilitated MPA uptake and metabolism.
The relatively small number of clinically evaluable patients may be construed as a limitation of our study. However, our sample size is consistent with that of other studies assessing MPA pharmacokinetics (32
). Evaluation of the distribution of the data supported the use of parametric statistics. The use of multivariable linear and logistic regression was done in consideration of the exploratory nature of this initial study, as the investigators assessed that this statistical approach would allow for adjustment for differences between samples at baseline. Another limitation may be that disease activity scores were measured in a retrospective fashion. However, cSLE documentation was done using standard clinic forms and a standardized laboratory panel was ordered during follow-up. This limited the amount of missing data and allowed for more uniform scoring of disease activity, reducing potential measurement errors. Response to MMF may also vary according to cSLE organ involvement. Additionally, all patients enrolled in this study had stable renal function, thus MPA-PK and MPA-PD unlikely changed during the time of MMF therapy.
Given its exploratory nature, the study did not account for concurrent cSLE medications, particularly prednisone, which may influence disease activity, response to MMF, and MPA metabolism. Nonetheless, our findings of the relationship between MPA exposure and response of MMF therapy are well in line with some other studies (24
), supporting the relevant of our findings that this might also be true for cSLE.
Our data may be interpreted as initial evidence that personalized dosing may be preferable in cSLE therapy to optimize response to MMF, thus necessitating a similar method of therapeutic drug monitoring such as that which is in current practice for solid organ transplant recipients. Obviously, such an observation will need to be formally tested under consideration of concurrent medication and patient adherence.