USE OF MTOR INHIBITORS AND MPA II

G. Basu¹, V.M. Annapandian¹, B.S. Matthew², K. Saravanakumar², A. Mohapatra¹, V.G. David¹, M. Sundaram¹, S. Varughese¹, D.H. Fleming², V. Tamilarasi¹, C.K. Jacob¹, G.T. John^1
1Nephrology, Christian Medical College, Vellore, Vellore/INDIA, ²Clinical Pharmocology, Christian Medical College, Vellore, Vellore/INDIA

Body: Background: Weight based dose of mycophenolate has been recommended for renal transplantation. Aim: To determine the relationship between the outcome events and weight adjusted mycophenolate (MPA) dose and drug exposure (AUC) among renal allograft recipients. Patients & methods: Renal allograft recipients, who underwent transplantation at Christian Medical College Vellore, between January 2003 and December 2009, and received mycophenolate mofetil (MMF) /sodium (MPS) along with prednisolone and tacrolimus, were studied. Extrapolated MPA-AUC_0-12h were measured after transplant ( between D5-10, at third month, sixth month, one year, later than one year and ad-hoc)by HPLC and the MMF/MPS dose were adjusted to maintain it between 30-60mg.h/L. The cumulative drug exposure and MPA dose and dose controlled AUC (Dc-AUC = MPA-AUC_0-12h/Dose_mg/Kg) were calculated up to the day of outcome events (rejections, infections, leucopenia or diarrhea) by applying trapezoidal rule, for the event-cases and respective controls. The difference of the mean cumulative drug exposure and dose between the cases and controls was analyzed. Results: Of the 235 renal allograft recipients (mean age 36.6±12.1 years; M:F=3:1) 90.6% received renal allografts from living related donors (with HLA AB ≥2 Ag match – 66.8%) and 9.4% from deceased donors. Most patients received induction therapy (74.5%)(predominantly basiliximab) and prednisolone with tacrolimus (83.0%) and MMF (51.1%) or MPS (48.9%). The recipients were followed up for a mean of 24.9±13.5 months. The mean serum creatinine (mg/dl) was 1.26±0.50 at 1 month, 1.21±0.32 at 6 months, 1.24±0.38 at 1 year, 1.27±0.41 at 2 years and 1.35±0.1 at 5 years post transplant. Patients switched from MPA to Azathioprine (9.4%) at a median of 4.9 (2.6-38.3) months after transplantation predominantly due to financial reasons (6.8%) and diarrhea (2.6%). At the first week, three months, six months, one year and later than one year respectively, the mean dose were (38.6±8.1, 39.4±13.7, 29.3±9.5, 24.9±8.7 and 24.1±10.1 mg/kg), the mean MPA-AUC_0-12h were (38.1±16.5, 59.0±28.1, 56.9±23.9, 52.7±18.3 and 50.3±18.2 mg.h/L). Overall, patients taking MPS achieved significantly higher Dc-AUC than MMF (2.0±1.0 vs. 1.7±1.1 Kg.h/L: p<0.001). The cumulative exposure (MPA-AUC_0-12h) till the event was significantly lower among the rejecters (16.5%) compared to the non rejecters (37.5±17.7 vs. 44.5±8.2 mg.h/L: p=0.027), but not the cumulative dose or Dc-AUC. This difference persisted even for early rejections (<3 months: 9.4%) and after controlling for the effect of induction. The cumulative MPA dose and exposure were not significantly different between patients who developed urinary tract infections (20.0%), CMV disease (8.5%), Herpes infections (5.5%), BK virus nephropathy (2.1%), systemic mycoses (2.6%) or leucopenia (21.7%) and their respective controls. However, among patients who developed diarrhea (11.1%) higher cumulative exposure (51.4±22.2 vs. 48.3±6.5 mg.h/L: p=0.494) with a significantly lower cumulative dose (31.8±8.3 vs. 35.7±4.8 mg/kg: p=0.043) was observed. Conclusion: Among Indian renal allograft recipients, despite use of similar weight based dose of MPA salts, patients who achieved lower MPAAUC_0-12h (even within therapeutic range of 30-60mg.h/L) were at a higher risk of suffering rejections. Therapeutic drug monitoring of MPA during the early post transplant period is helpful in reducing rejection rates among Indian allograft recipients.

Disclosure: All authors have declared no conflicts of interest.