Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial.
Cross-Over Studies
Double-Blind Method
Drug Interactions
Enzyme Inhibitors
/ therapeutic use
Female
Humans
Kidney
/ drug effects
Kidney Transplantation
/ methods
Liver Transplantation
/ methods
Male
Middle Aged
Mycophenolic Acid
/ therapeutic use
Pantoprazole
/ therapeutic use
Prospective Studies
Proton Pump Inhibitors
/ therapeutic use
drug interaction
enteric-coated mycophenolate sodium
kidney transplant
mycophenolate
mycophenolic acid
pharmacokinetic
proton-pump inhibitor
Journal
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
ISSN: 1460-2385
Titre abrégé: Nephrol Dial Transplant
Pays: England
ID NLM: 8706402
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
30
01
2020
accepted:
31
03
2020
entrez:
10
6
2020
pubmed:
10
6
2020
medline:
24
11
2020
Statut:
ppublish
Résumé
Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.
Sections du résumé
BACKGROUND
Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure.
METHODS
A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study).
RESULTS
Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group.
CONCLUSIONS
The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.
Identifiants
pubmed: 32516810
pii: 5855235
doi: 10.1093/ndt/gfaa111
doi:
Substances chimiques
Enzyme Inhibitors
0
Proton Pump Inhibitors
0
Pantoprazole
D8TST4O562
Mycophenolic Acid
HU9DX48N0T
Banques de données
ANZCTR
['ACTRN12611000316909']
Types de publication
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1060-1070Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.