IMPACT OF OMEPRAZOLE ON MYCOPHENOLIC ACID PHARMACOKINETICS IN ADULT KIDNEY TRANSPLANT RECIPIENTS

CLINICAL IMMUNOSUPPRESSION - KIDNEY LATE

P.Y.W. Fan¹, K.A. Barraclough², N.M. Isbel³, K.J. Lee⁴, D.W. Johnson⁵, D. Leary⁶, C.E. Staatz^7
1School Of Pharmacy, University of Queensland, Brisbane/QLD/AUSTRALIA, ²Nephrology, Princess Alexandra Hospital, Brisbane/AUSTRALIA, ³Department Of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane/QLD/AUSTRALIA, ⁴Pharmacy, University of Queensland, Brisbane/AUSTRALIA, ⁵Department Of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane/AUSTRALIA, ⁶Nephrology, Princess Alexandra Hospital, Brisbane/QLD/AUSTRALIA, ⁷School Of Pharmacy, University of Queensland, Brisbane/AUSTRALIA

Body: Introduction: Mycophenolic acid (MPA), an anti-proliferative antimetabolite, is widely used in kidney transplantation to prevent allograft rejection. Although MPA is more efficacious than other anti-metabolite immunosuppressants, its use is limited by its drug adverse effects, mainly gastrointestinal disturbances. Most organ transplant recipients, who develop gastrointestinal adverse effects related to MPA, are treated with gastro-protective medications. Previous studies have reported that the proton pump inhibitors (PPIs) lansoprazole and rabeprazole decrease MPA exposure after mycophenolate mofetil (MMF) intake. The influence of omeprazole on MPA pharmacokinetics after kidney transplant has not been evaluated. Our study aims to investigate the impact of omeprazole therapy on MPA pharmacokinetics in kidney transplant recipients receiving stable maintenance immunosuppressive doses of MMF, tacrolimus and prednisolone. Methods: Data were collected from 42 kidney transplant recipients between August 2009 and January 2010 who were at least one month post-transplant. Blood samples were collected from subjects at 4 time points: 0 (pre-dose; C₀), 1 (C₁), 2 (C₂) and 4 (C₄) hours post-dose and MPA plasma concentrations were measured using high-performance liquid chromatography. The dose of MMF on the day of blood sampling was recorded. MPA area under the concentration-time curve (AUC) from 0 to 4 hours post-dose (AUC_0-4) was calculated using the linear trapezoidal rule. MPA AUC from 0 to 12 hours post-dose (AUC_0-12) was estimated using a validated two-point limited sampling strategy. Statistical differences in patient clinical characteristics and dose-adjusted MPA exposure between patients receiving omeprazole and ranitidine were evaluated using a Student’s T-test or Wilcoxon-signed rank test. P-values of <0.05 were considered significant. Results: Key study results are presented in the table 1 below. No significant differences were observed in patient age, weight and biochemical data between the two patient cohorts. There were no significant differences in the MMF single dose, dose-adjusted MPA concentrations (C₀, C₁, C₂ and C₄), dose-adjusted MPA AUC_0-4 and dose-adjusted MPA-AUC_0-12 between the two groups. There was a trend towards a lower dose-adjusted MPA exposure in those who received omeprazole compared to ranitidine co-therapy. Table 1. Pharmacokinetic parameters of MPA with Omeprazole and Ranitidine co-therapy

	Omeprazole	Ranitidine (control)	P-value
Number of patients	21	21
MMF single dose (g)	0.93 ± 0.21	0.95 ± 0.20	0.88
Dose-adjusted MPA C0 (ug/L/g)	2.43 ± 1.92	2.65 ± 1.52	0.39
Dose-adjusted MPA C1 (ug/L/g)	6.33 ± 3.91	7.63 ± 5.47	0.61
Dose-adjusted MPA C2 (ug/L/g)	5.93 ± 2.99	6.14 ± 3.38	0.97
Dose-adjusted MPA C4 (ug/L/g)	3.09 ± 2.19	3.67 ± 1.19	0.05
Dose-adjusted AUC0-4 (ug.h/L/g)	19.54 ± 8.67	21.84 ± 8.46	0.31
Dose-adjusted AUC0-12 (ug.h/L/g)	38.50 ± 20.43	41.99 ± 11.20	0.14

Values are shown in mean ± SD Conclusion: Our study demonstrates that co-administration of omeprazole with MMF in adult kidney transplant recipients does not significantly influence the pharmacokinetics of MPA. Larger studies are required to further examine pharmacokinetic interactions between MMF and different PPIs.

Disclosure: All authors have declared no conflicts of interest.