Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation.
BACKGROUND
Dosing of mycophenolate mofetil (MMF) must be lower in combination therapy with Tacrolimus (Tac) than with Cyclosporine. One study with mostly adolescent recipients recommended an MMF dose of 250 mg/m2 BID. Because this dose resulted in low area-under-the-curve (AUC) in our infant population, we retrospectively analyzed all available pharmacokinetic (PK) profiles in pediatric renal transplant patients on MMF plus Tac therapy to propose appropriate MMF dosing in pediatric patients of all ages.


METHODS
Forty-four PK profiles were performed in 27 patients (median age, 11.6 years; range, 1.8-20.7 years). The investigations were performed at a median of 299 days (range, 24-3424) after transplantation. Ten patients were converted to Tac plus MMF, all others received this as primary therapy. For patients with repeated measurements, we calculated the average AUC and doses. We used first-order PK modeling to calculate the doses for a mycophenolic acid (MPA) AUC of 60 ug*h/mL and a Tac AUC of 150 ng*h/mL.


RESULTS
The mean Tac dose was 2.6 +/- 1.2 mg/m2/d or 0.086 +/- 0.038 mg/kg/d, resulting in an average AUC of 120.6 +/- 30.4 ng*h/mL. The MMF dose was not normally distributed; the median dose was 549 mg/m2/d (range, 146-1413) and the median MPA AUC was 49.8 ug*h/mL (range, 26.7-156.0). The mean dose for a Tac AUC of 150 ng*h/mL was 3.50 +/- 1.77 mg/m2/d (0.117 +/- 0.058 mg/kg) and was independent of age or time after transplantation. By contrast, we found a negative relationship between the dose per m2 (r2 = 0.29; P = 0.0038) or per kg (r2 = 0.58; P < .0001) required for an MPA AUC of 60 ug*h/mL and patient age. Converted and primary patients behaved identically. The dosing requirement decreased from 500 mg/m2 BID in 2-year-old patients to 250 mg/m2 in adolescents. There was substantial interpatient variability of 44%.


CONCLUSIONS
Higher MMF doses are required for young children. Our data suggest a starting dose for infants of 500 mg/m2 BID, with PK monitoring of MPA due to substantial interpatient variability.
Filler
G
G
Division of Pediatric Nephrology, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada. filler@cheo.on.ca
Foster
J
J
Berard
R
R
Mai
I
I
Lepage
N
N
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D007223:Infant; D016030:Kidney Transplantation / Q000276:immunology; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012189:Retrospective Studies; D012449:Safety; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus