Age-related variability of mycophenolate mofetil exposure in stable pediatric liver transplant recipients and influences of donor characteristics.
Despite the increasing use of mycophenolate mofetil (MMF) in pediatric liver transplantation recipients, data on MMF pharmacokinetics in this population are relatively scattered. This pilot study was performed to explore whether recipient age-related factors, in conjunction with donor factors, can explain variability in mycophenolic acid (MPA) exposure. Thirty-four MPA pharmacokinetic profiles were performed in 20 stable pediatric liver transplantation recipients (median age, 12 years; range, 1-18 years; median delay after liver transplant, 88 months; range, 3-179 months). Ten children were converted to MMF; the others received MMF as a primary immunosuppressive regimen. MMF was used in combination with tacrolimus. Plasma MPA concentrations were analyzed samples collected at 0, 1, 3, and 6 hours after MMF administration using the enzyme multiplied immunotechnique immunoassay. The median MMF dose was 431 mg/m2 per day (range, 189-833 mg/m2 per day) leading to a median estimated MPA-AUC0-12h of 27 mg/h/L (range, 17-79 mg/h/L). Dose-normalized MPA-AUCs were characterized by high interpatient variability. Young children receiving a liver from a pediatric donor had lower MPA exposure compared with those receiving liver from an adult donor. No correlation was seen between MPA-C0 and MPA-AUC 0-6h in infants, whereas this correlation was significant but moderate in older children. The interpatient variability of MPA exposure observed with this pilot study is an argument for developing therapeutic drug monitoring-based dose adaptation strategies in pediatric liver transplantation recipients. A marked MPA underexposure was observed among young children receiving livers from pediatric donors, indicating that higher doses (mg/m2 of body surface area) might be required to reach the same MPA exposure as in adolescents.
Parant
François
F
Hospices Civils de Lyon, Hôpital Edouard Herriot, Pharmacologie Spécialisée, Fédération de Biochimie, Lyon, France. francois.parant@chu-lyon.fr
Rivet
Christine
C
Boulieu
Roselyne
R
Gagnieu
Marie-Claude
MC
Dumortier
Jérôme
J
Boillot
Olivier
O
Lachaux
Alain
A
D000293:Adolescent; D000375:Aging; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000097:blood; D017248:Enzyme Multiplied Immunoassay Technique; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use*; D007223:Infant; D016031:Liver Transplantation / Q000706:statistics & numerical data*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D010865:Pilot Projects; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D014019:Tissue Donors / Q000706:statistics & numerical data*
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011355:Prodrugs; D009173:Mycophenolic Acid