The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue.

BACKGROUND: Mycophenolic acid (MPA) is used widely to prevent graft rejection in kidney-transplant patients. Therapeutic drug monitoring (TDM) in plasma requires an invasive procedure that is inconvenient, especially in pediatric patients. TDM in saliva is a more convenient non-invasive alternative compared with plasma. METHODS: A population physiologically based pharmacokinetic (Pop-PBPK) model of mycophenolate mofetil (MMF) and MPA with enterohepatic recycling was built and verified using previously published plasma, saliva, and kidney biopsy data in healthy and kidney-transplant adult patients. The verified model was then used to predict experimentally observed plasma and saliva MMF and MPA TDM data in Jordanian pediatric kidney transplant patients measured using LC-MS/MS. A correlation was established between plasma and saliva exposures in pediatrics. RESULTS: The developed LCMS was sensitive to both MMF and MPA in plasma and saliva. The developed Pop-PBPK model predicted well the previously reported MMF and MPA levels in plasma, saliva, and kidney tissue and those observed in the current study (more than 75% of observed data points were within 90% predictive interval of population simulations). A statistically significant correlation was found between plasma and saliva exposures for both MMF (Pop-PBPK predicted and observed) and MPA (Pop-PBPK predicted). CONCLUSION: Both MPA and MMF can be classified as class III compounds in the Salivary Excretion Classification System. Saliva is an alternative body fluid to plasma that can be used for TDM of MPA and MMF in kidney-transplant patients in pediatrics. Exposure to MPA and MMF in plasma, saliva, and kidney tissue was reliably predicted using the developed Pop-PBPK model.