Proton pump inhibitor co-medication reduces mycophenolate acid drug exposure in heart transplant recipients.
BACKGROUND
Proton pump inhibitors (PPIs) are often prescribed for gastrointestinal discomfort after heart transplantation (HTx). This study investigates the impact of PPI use on mycophenolate acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) and tacrolimus (Tac).


METHODS
MPA post-dose plasma concentrations at 0 to 2 hours were obtained by high-performance liquid chromatography (HPLC) in 21 patients on pantoprazole 40 mg/day (PPI group) and 12 patients not on pantoprazole (control group). In a subgroup, MPA plasma concentrations at 0 to 12 hours were measured to evaluate full MPA area-under-the-curve (AUC) measurements.


RESULTS
In the PPI group, the mean daily MMF dose was 1,912 +/- 1,023 mg with mean pre-dose serum concentrations (C(0)) of 1.9 +/- 1.4 mg/liter, without a significant difference from controls. Mean post-dose MPA concentrations at 30 minutes (C(0.5h)) were significantly higher in the control group (control, 17.9 +/- 11.5 mg/liter; PPI, 6.7 +/- 4.6 mg/liter; p < 0.001). One- and 2-hour (C(1h, 2h)) MPA concentrations were persistently higher in the control group (1 hour: control, 13.8 +/- 9.1 mg/liter; PPI, 7.7 +/- 4.1 mg/liter; 2 hours: control, 7.6 +/- 4.2; PPI, 5.0 +/- 2.8 mg/liter; p < 0.05). In the subgroup with full AUC measurements, the control group had higher MPA levels 12 hours after dosing (C(12h): control, 3.3 +/- 2.4 mg/liter; PPI, 1.6 +/- 1.3 mg/liter; p < 0.05) and a significantly higher dose-adjusted AUC C(0-3h) (control, 59.5 +/- 20.7 mg/liter; PPI, 41.7 +/- 23.4 mg/liter; p < 0.05). In the subgroup, the maximum plasma concentration of mycophenolic acid (MPA C(max)) in the PPI group was significantly lower (10.1 +/- 4.7 mg/liter) than in the control group (45.5 +/- 53.5 mg/liter, p < 0.0001), whereas t(max) revealed no differences (control: 1.1 +/- 0.77 hours; PPI: 1.1 +/- 0.97 hours). Furthermore, a clear trend for more acute rejection episodes (AREs) and more transplant vasculopathy (TVP) was found in the PPI group.


CONCLUSIONS
Patients with PPI co-medication show significantly lower MPA plasma concentrations, possibly due to decreased absorption. Therapeutic drug monitoring allows identification of patients with decreased MMF drug exposure who might be at risk for acute rejection.
Kofler
Sieglinde
S
Department of Cardiac Surgery, University Hospital Grosshadern, Ludwig Maximilians University, Marchioninistrasse 15, Munich, Germany. sieglinde.kofler@med.uni-muenchen.de
Deutsch
Marcus-André
MA
Bigdeli
Amir K
AK
Shvets
Nataliya
N
Vogeser
Michael
M
Mueller
Thomas H
TH
Meiser
Bruno
B
Steinbeck
Gerhard
G
Reichart
Bruno
B
Kaczmarek
Ingo
I
D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005767:Gastrointestinal Diseases / Q000188:drug therapy / Q000209:etiology; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D007166:Immunosuppressive Agents; D054328:Proton Pump Inhibitors; D000077402:Pantoprazole; D009173:Mycophenolic Acid; D016559:Tacrolimus