Proton Pump Inhibitors do not Interact with the Immunosuppressant Enteric-Coated Mycophenolate Sodium

Transcription

1 Proton Pump Inhibitors do not Interact with the Immunosuppressant Enteric-Coated Mycophenolate Sodium S. Kofler, C. Wolf, Z. Sisic, J. Behr, M. Vogeser, M. Shipkova, B. Meiser, G. Steinbeck, B. Reichart, I. Kaczmarek University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany No conflict of interest

2 Aim of the study This prospective study investigates the impact of proton pump inhibitors (PPI) on mycophenolate acid (MPA) pharmacokinetics in heart and lung transplant recipients receiving Enteric-Coated Mycophenolate Sodium (EC-MPS) and Tacrolimus (Tac).

3 Pharmacokinetics of Mycophenolates Currently two mycophenolate compounds are available: Mycophenolate Mofetil (MMF, Cellcept ) and Enteric-Coated Mycophenolate Sodium (EC-MPS, Myfortic ) They are specific inhibitors of T- and B-cell proliferation by reversibly inhibiting inosine monophosphate dehydrogenase (IMPDH), the key enzyme of the novo purine synthesis in activated lymphocytes.

4 In previous studies we could demonstrate that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF) by 34% area under the concentration time curve (AUC). Kofler S et al. Am J Transplant 2009;9(7): Kofler S et al. J Heart and Lung Transplant 2009;28(6): Because gastrointestinal side effects are common after organ transplantation (40%), we investigated the effect of PPI on MPA levels in patients receiving EC- MPS.

5 Pathway of Absorption MMF MMF is converted into his active metabolite MPA in a ph dependent mechanism in the stomach. The gastric acid secretion inhibitory effect of PPI with a gastric ph>4.5 decreases the elution of MMF. EC-MPS EC-MPS is an enteric-coated formulation of MPA developed with the aim of minimizing upper gastrointestinal side effects. EC-MPS remains intact in the acidic environment of the stomach and dissolves in his active metabolite MPA after reaching the neutral ph>5.6 to 6.0 in the small intestine.

6 Study Design Immunosuppression Tacrolimus (5-14 ng/ml) Enteric-Coated Mycophenolate Sodium (EC-MPS twice daily) After the first measurements the PPI treatment with 40 mg Pantoprazole was stopped and the parameters were measured again one month after Pantoprazole withdrawal. EC-MPS was continued with the same dose twice daily. MPA plasma concentrations and IMPDH activity were measured at the following time points baseline= C 0h 30 minutes after intake= C 0.5h 1 hour after intake= C 1h 2 hours after intake= C 2h 3 hours after intake= C 3h 4 hours after intake= C 4h

7 Clinical characteristics of 21 heart or lung transplant recipients with PPI medication and after withdrawal. Values are reported as mean±sd or %. There were no significant differences.

8 Pharmacokinetic parameters of EC-MPS under PPI medication and after withdrawal in heart and lung transplant recipients. Values are reported as mean ± SD. There were no significant differences.

9 MPA plasma concentration (mg/l) Proton Pump Inhibitors do not Interact with the Immunosuppressant Enteric-Coated Mycophenolate Sodium Time (hours) Mean MPA plasma concentrations at different time points comparing patients with PPI treatment and after PPI withdrawal (n=21). Values are reported as mean SD. There are no significant differences.

10 IMPDH activity µmol/s*mol AMP Proton Pump Inhibitors do not Interact with the Immunosuppressant Enteric-Coated Mycophenolate Sodium Time (hours) IMPDH activity in mol/s mol AMP at different time points comparing patients with PPI treatment and after PPI withdrawal (n=21). Values are reported as mean SD. There are no significant differences.

11 Pharmacokinetic parameters of EC-MPS under PPI therapy and after withdrawal: Values are reported as mean ± SD. There are no significant differences. with PPI no PPI IMPDH activity AUC 4h ( mol/s*mol AMP)*h MPA concentration AUC 4h (mg/l*h) MPA concentration C max (mg/l) Four hours areas under the concentration time curve (AUC) were calculated for MPA concentrations and IMPDH activities; MPA C max =maximal MPA concentration;

12 Proton Pump Inhibitors do not Interact with the Immunosuppressant Enteric-Coated Mycophenolate Sodium Results MPA concentrations and IMPDH activities did not reveal any significant differences during PPI treatment and after withdrawal. MPA AUC and IMPDH AUC based on an algorithm for a 5-point limited sampling strategy were without significant differences. MPA C max (maximal MPA concentration) and the time until C max was reached (T max ) were not different between the two time points.

13 Proton Pump Inhibitors do not Interact with the Immunosuppressant Enteric-Coated Mycophenolate Sodium Conclusion We could not find an influence of pantoprazole on EC-MPS pharmacokinetics as we could demonstrate for MMF in our previous investigation. A further prospective, large, cross over study is planned to support these preliminary results. Given that MPA exposure correlates with the incidence of acute rejection episodes and transplant vasculopathy, these findings may have clinical implications.

14 Kofler S et al. J Heart and Lung Transplant 2009;28(6):

15 Pharmacokinetic parameters of EC-MPS under PPI therapy and after withdrawal: Values are reported as mean ± SD and 95% of CI for the mean. There are no significant differences. Four hours areas under the concentration time curve (AUC) were calculated for MPA concentrations and IMPDH activities; MPA C max =maximal MPA concentration; MPA T max =timepoint of MPA C max ; IMPDH min = lowest IMPDH activity; IMPDH T min = timepoint with the lowest IMPDH activity.