A limited sampling model for estimation of total and unbound mycophenolic acid (MPA) area under the curve (AUC) in hematopoietic cell transplantation (HCT).
OBJECTIVE
Renal transplant patients with suboptimal mycophenolic acid (MPA) areas under the curves (AUCs) are at greater risk of acute rejection. In hematopoietic cell transplantation, a low MPA AUC is also associated with a higher incidence of acute graft versus host disease. Therefore, a limited sampling model was developed and validated to simultaneously estimate total and unbound MPA AUC0-12 in hematopoietic cell transplantation patients.


METHODS
Intensive pharmacokinetic sampling was performed at steady state between days 3 to 7 posttransplant in 73 adult subjects while receiving prophylactic mycophenolate mofetil 1 g per 12 hours orally or intravenously plus cyclosporine. Total and unbound MPA plasma concentrations were measured, and total and unbound AUC0-12 was determined using noncompartmental analysis. Regression analysis was then performed to build IV and PO, total and unbound AUC0-12 models from the first 34 subjects. The predictive performance of these models was tested in the next 39 subjects.


RESULTS
Trough concentrations poorly estimate observed total and unbound AUC0-12 (r<0.48). A model with 3 concentrations (2-, 4-, and 6-hour post start of infusion) best estimated observed total and unbound AUC0-12 after IV dosing (r>0.99). Oral total and unbound AUC0-12 was more difficult to estimate and required at least 4 concentrations (0-, 1-, 2-, and 6-hour post dose) in the model (r>0.85). The predictive performance of the final models was good. Eighty-three percent of IV and 70% of PO AUC0-12 predictions fell within +/-20% of the observed values without significant bias.


CONCLUSIONS
Trough MPA concentrations do not accurately describe MPA AUC0-12. Three intravenous (2-, 4-, 6-hour post start of infusion) or 4 oral (0-, 1-, 2-, and 6-hour post dose) MPA plasma concentrations measured over a 12-hour dosing interval will estimate the total and unbound AUC0-12 nearly as well as intensive pharmacokinetic sampling with good precision and low bias. This approach simplifies AUC0-12 targeting of MPA post hematopoietic cell transplantation.
Ng
Juki
J
Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.
Rogosheske
John
J
Barker
Juliet
J
Weisdorf
Daniel
D
Jacobson
Pamala A
PA
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage; D016903:Drug Monitoring / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008954:Models, Biological; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid