title: Population pharmacokinetics of unbound mycophenolic acid in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation.
abstract: Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmacokinetics were well described by a 2-compartment model with linear elimination and first-order absorption. The important clinical covariates affecting unbound MPA pharmacokinetics were weight, estimated creatinine clearance, and total bilirubin. Unbound MPA clearance was reduced, and exposure (AUC(0-8)) increased in individuals with decreased renal function. In individuals with severe hepatic dysfunction (total bilirubin >10 mg/dL) unbound MPA clearance was approximately 3-fold lower compared with patients with normal to mild hepatic impairment. In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression.
authors: Department of Clinical Pharmacy, University of California San Francisco, School of Pharmacy, 521 Parnassus Ave, C-152, Box 0622, San Francisco, CA 94143-0622, USA.
authors: Hyewon
authors: H
authors: Kim
authors: Janel
authors: J
authors: Long-Boyle
authors: Nancy
authors: N
authors: Rydholm
authors: Paul J
authors: PJ
authors: Orchard
authors: Jakub
authors: J
authors: Tolar
authors: Angela R
authors: AR
authors: Smith
authors: Pamala
authors: P
authors: Jacobson
authors: Richard
authors: R
authors: Brundage
mesh_terms: D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007223:Infant; D008297:Male; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood* / Q000493:pharmacokinetics; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid