Pharmacokinetics and pharmacodynamics of intensified versus standard dosing of mycophenolate sodium in renal transplant patients.
OBJECTIVE
Adequate early mycophenolic acid (MPA) exposure is an important determinant for effective rejection prophylaxis. This pharmacokinetic study investigated whether an intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) could achieve higher mycophenolic acid (MPA) exposure early after transplantation versus a standard dosing regimen.


METHODS
De novo kidney transplant recipients (n = 75) who were treated with basiliximab induction and cyclosporine were randomly assigned to receive EC-MPS as either standard dosing (1440 mg/d; n = 37) or intensified dosing (days 0 through 14: 2880 mg/d; days 15 through 42: 2160 mg/d; followed by 1440 mg/d; n = 38). Full 12-hour pharmacokinetic and pharmacodynamic profiles were taken at six time points during the first 3 months. Exploratory analysis of inosine monophosphate dehydrogenase (IMPDH) activity was also performed for better understanding of the pharmacokinetic-pharmacodynamic relationship between MPA exposure and IMPDH activity in the early posttransplantation period. Preliminary efficacy parameters, safety, and tolerability were assessed.


RESULTS
Exposure to MPA was significantly higher on days 3 and 10 after transplantation in the intensified versus standard EC-MPS group, with 52.9 versus 22.2% (P < 0.05) of patients reaching MPA exposure >40 mg/h per L in the first week. The intensified regimen resulted in significantly lower IMPDH activity on day 3 after transplantation, and the overall safety was comparable for both groups.


CONCLUSIONS
These pharmacokinetic and safety data support further research on the hypothesis that early adequate MPA exposure could improve clinical outcome.
Department of Nephrology, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. petra.glander@charite.de
Petra
P
Glander
Claudia
C
Sommerer
Wolfgang
W
Arns
Toofan
T
Ariatabar
Stefan
S
Kramer
Eva-Maria
EM
Vogel
Maria
M
Shipkova
Wolfgang
W
Fischer
Martin
M
Zeier
Klemens
K
Budde
D000284:Administration, Oral; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D019540:Area Under Curve; D000077552:Basiliximab; D016009:Chi-Square Distribution; D016572:Cyclosporine / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005260:Female; D005858:Germany; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007168:IMP Dehydrogenase / Q000097:blood; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D010865:Pilot Projects; D011446:Prospective Studies; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D013608:Tablets, Enteric-Coated; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D013608:Tablets, Enteric-Coated; D016572:Cyclosporine; D000077552:Basiliximab; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid