Mycophenolic Acid Therapeutic Drug Monitoring in De Novo Renal Transplant Patients and the Related Outcomes

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Abstract

Introduction

Mycophenolic acid (MPA) monitoring in renal transplant has been applied variably among transplant centers due to non-uniformity of transplant outcome benefits in concentration-controlled MPA prescription versus a fixed dosing approach. We reviewed the MPA trough and area under the curve (AUC) levels in our de Novo renal transplant patients and investigated for correlations between MPA levels with acute transplant outcomes, i.e. concomitant biopsy proven acute rejections (BPAR), MPA related side effects, such as infections (bacterial or viral), non-infective diarrhoea, anemia, neutropaenia, and thrombocytopaenia.

Materials and Methods

This is a retrospective single centre review of all MPA TDM results performed from 1st Jan 2011 till 31st September 2017, which were measured as per protocol within the first 90 days post-transplant, in patients receiving mycophenolate mofetil (MMF) and tacrolimus co-therapy. MPA TDM results were measured using HPLC (High Performance Liquid Chromatography) assay and MPA AUC levels were calculated using the trapezoidal method with MPA levels measured at 0, 1, 2 and 4 hours of MPA dosing. All relevant events that occured within 2 weeks from the time of MPA measurement were included and analysed.

Results and Discussion

Our study population of 227 was 85.9% Caucasian, with a mean age of 50±13 years (ranged 19 to 76), with a gender distribution of 86 females and 141 males. The mean MPA AUC and trough levels were 46.5±21.5mg/L.h and 2.6±4.4mg/L respectively, with mean MMF dose of 1998±360mg/day, which was 26.5±7.6mg/kg/day after being weight adjusted. With fixed MMF dosing, 20.3% of our patients had MPA AUC <30mg/L.h (table 1a), while 26.9% had MPA trough <1.6mg/L (table 1b).

Results and Discussion

Incidence of BPAR was 10.1% while incidence of MPA related side effects ranged from 1.8% to 12.8% (table 2).

Results and Discussion

BPAR incidence was not reduced in patients with MPA trough ≥1.6mg/L or MPA AUC ≥30mg/L.h but had numerically reduced odds ratio (OR) if MPA AUC ≥40mg/L.h or MPA trough ≥1.9mg/L was applied (table 3).

Results and Discussion

MPA AUC ≥60mg/L.h was statistically associated with increased risk of viral infections, namely CMV and BKV viraemia, with OR of 1.95 (95% CI 1.08-3.50, p=0.043). There is also increased OR for neutropenia and non infective diarrhoea (not statistically significant). Otherwise, MPA trough ≥4.0mg/L had a non-statistically-significant increase in OR for viral infections, neutropenia, thrombocytopenia, and non-infective diarrhoea (table 4).

Conclusion

The significantly increased OR for viral infection with MPA over-exposure and tendency for reduced BPAR with higher MPA levels suggested a concentration-response-toxicity effect of MPA in de novo renal transplantation. Further studies are needed to strengthen our hypothesis and to identify the optimal drug therapeutic range.

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