Population pharmacokinetics of total and free mycophenolic acid in plasma in paediatric patients with nephrotic syndrome including salivary concentrations and the pharmacodynamics.

BACKGROUND

Therapeutic drug monitoring (TDM) may optimize dosing of mycophenolate mofetil (MMF) in patients with nephrotic syndrome, but it is not routinely implemented. When performed, TDM typically relies on total mycophenolic acid (MPA) concentrations, although only unbound MPA is pharmacologically active. This study aimed to develop a population pharmacokinetic (PK) model characterizing the PK and pharmacodynamics (PD) of total and unbound MPA in plasma and saliva of paediatric nephrotic syndrome patients following oral MMF.

METHODS

PK/PD data from 62 children (47 full and 21 limited sampling curves) were analysed using nonlinear mixed-effects modelling.

RESULTS

A two-compartment model with first-order absorption best describes unbound MPA PK. Protein binding was captured using a nonlinear saturable binding equation. The final population PK parameter estimates (for unbound MPA) were absorption rate constant (ka), 1.81 h-1 (relative standard error (RSE): 8%); apparent clearance (Cl/F), 2550 L h-1 (RSE: 8%); apparent central volume (Vc/F), 1590 L (RSE: 27%); apparent peripheral volume (Vp/F), 239,000 L (RSE: 52%); apparent intercompartmental clearance (Q/F), 1940 L h-1 (RSE: 13%); maximal binding capacity (Bmax), 196 µmol (RSE: 44%); dissociation constant (Kd), 0.75 µmol L-1 (RSE: 49%). Saliva and unbound plasma MPA showed a proportional relationship (saliva/plasma ratio: 1.34, RSE: 24%). The PK-PD relationship between unbound MPA and inosine monophosphate dehydrogenase (IMPDH) activity was described by a sigmoid inhibitory effect model with a baseline parameter. The population estimates were baseline effect, 66.4 (RSE: 21%); unbound plasma concentration for 50% inhibition, 0.0251 (RSE: 27%); shape parameter, 0.559 (RSE:22%). A limited sampling strategy allowed acceptable prediction of unbound MPA area under the concentration-time curve from 0 to 12 hours (AUC0-12 h) but not IMPDH activity.

CONCLUSION

The developed model provides a foundation for model-informed precision dosing of MMF in children with nephrotic syndrome.