POPULATION PHARMACOKINETICS OF MYCOPHENOLIC ACID: A COMPARISON BETWEEN ENTERIC-COATED MYCOPHENOLATE SODIUM AND MYCOPHENOLATE MOFETIL IN RENAL TRANSPLANT RECIPIENTS

CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY

M. Outeda¹, P. Salvador¹, A. Lopez², I. Pedreira¹, C. Fernandez², A. Alonso², I. Martin^1
1Pharmacy Department, UNIVERSITY HOSPITAL OF A CORUÑA, A CORUÑA/SPAIN, ²Nephrology Department, UNIVERSITY HOSPITAL OF A CORUÑA, A CORUÑA/SPAIN

Body:
Background In Spain, there are two formulations with mycophenolate: Cellcept^® (mycophenolate mofetil-MMF) and Myfortic^® (enteric-coated mycophenolate sodium-EC-MPS). The aim of this study is 1) to determine and compare the pharmacokinetic profile of MMF and EC-MPS and 2) to assess the correlation between individual trough and 2-hour concentrations (C_trough and C₂) and the area-under-the-curve (AUC_0-12) to predict the exposure of mycophenolic acid (MPA) in a Spanish population of renal transplant recipients. Methods Prospective study of patients who underwent a cadaveric renal transplantation at University Hospital of A Coruña (Spain) between July 2009 and January 2010. All recipients were Spanish (Caucasian) and co-treated with tacrolimus and steroids. Pharmacokinetic profiles were obtained at two weeks and in the stable period (three months) posttransplant. All patients received the same MMF or EC-MPS dosage for at least 1 week before each profile. Dose correction of 360 mg of EC-MPS = 500 mg of MMF was applied. Blood samples were taken predose and 1, 2, 3, 4, 6 and 8 h after oral morning dose. Plasma levels were measured using EMIT on a VIVA^® Analyzer. AUC_0-12 was calculated using the linear trapezoidal rule. Statistical analysis was performed using SPSS 17.0.The Mann-Whitney U test was used to test for statistical differences (p<0.05). C_troug and C₂ of MPA were correlated to AUC_0-12 by correlation of determination (r²). Results Twenty-nine patients (14 with MMF/15 with EC-MPS, age 54±12 years, weight 74.9±16.2 kg) were included. The pharmacokinetic parameters are shown in table below.

	Early period		Stable period
	Cellcept®	Myfortic®	Cellcept®	Myfortic®
Dose/day (mg)	2000	1440	1000	720
Ctroug (ng/mL)	4.1 ± 2.6	4.3 ± 1.9	4.5 ± 3.2	5.7 ± 3.8
AUC0-12 (ng.h/mL)	74.3 (46-88)	76.4 (53-87)	33.6 (19-46)	61.1 (52-70)
AUC0-12/ Ctroug (r2)	0.922	0.893	0.973	0.73
AUC0-12/ C2 (r2)	0.303	0.692	0.600	0.350
tmax (h)	1	2-6	1	2-6

In the early period, the analysis of the curves showed similar values (p= 0.893), while in the stable period the AUC_0-12 of MMF showed a significant decrease (p= 0.016). Conclusions In early transplant, with the administration of equivalent doses of MMF and EC-MPS similar levels of exposure to MPA were observed. The initial doses were progressively reduced for MMF and EC-MPS, obtaining an average dose reduction of 50% in the stable period. In the stable period, both formulations provided similar predose levels. However, the degree of exposure for EC-MPS increased significantly, revealing that the AUCs for the two medications were not comparable. For both medications, trough level monitoring is a good way to predict degree of exposure (AUC_0-12), MMF presenting a better correlation.

Disclosure: All authors have declared no conflicts of interest.