Limited Sampling Strategy of Mycophenolic Acid in Adult Kidney Transplant Recipients: Influence of the Post‐Transplant Period and the Pharmacokinetic Profile

Abstract

We aimed to develop an accurate and convenient LSS for predicting MPA-AUC(0-12 hours) in Tunisian adult kidney transplant recipients whose immunosuppressive regimen consisted of MMF and tacrolimus combination with regards to the post-transplant period and the pharmacokinetic profile. Each pharmacokinetic profile consisted of eight blood samples collected during the 12-hour dosing interval. The AUC(0-12 hours) was calculated according to the linear trapezoidal rule. The MPA concentrations at each sampling time were correlated by a linear regression analysis with the measured AUC(0-12). We analyzed all the developed models for their ability to estimate the MPA-AUC(0-12 hours). The best multilinear regression model for predicting the full MPA-AUC(0-12 hours) was found to be the combination of C1, C4, and C6. All the best correlated models and the most convenient ones were verified to be also applicable before 5 months after transplantation and thereafter. These models were also verified to be applicable for patients having or not the second peak in their pharmacokinetic profiles. For practical reasons we recommend a LSS using C0, C1, and C4 that provides a reasonable MPA-AUC(0-12 hours) estimation.

Pharmacokinetics of Mycophenolate Mofetil and Development of Limited Sampling Strategy in Early Kidney Transplant Recipients

“…The LSS technique has been applied in estimating the MPA exposure of MMF capsule in the past decades. For MMF capsule, substantial research has shown that an LSS can predict MPA-AUC 0-12 h in different populations after transplantation ( Kuypers et al, 2010 ; Mathew et al, 2010 ; Saint-Marcoux et al, 2011 ; Chaabane et al, 2013 ). However, those models cannot accurately estimate the AUC values of MMF dispersible tablet in most of our patients.…”

“…Some researches have shown that the trough level of MPA may be correlated to the patient’s outcomes in kidney transplant recipients ( Borrows et al, 2006 ; Miura et al, 2011 ). However, many studies have indicated a poor correlation between single-point concentrations and MPA-AUC 0-12 h ( Barraclough et al, 2012a ; Chaabane et al, 2013 ; Yamaguchi et al, 2013 ; Cai et al, 2015 ; Jia et al, 2017 ). The present study also revealed the same result.…”

“…The MPA-AUC 0-12 h has been recommended as the best marker for the MMF dose adjustment to achieve optimal efficacy and keep the toxicity to minimum in clinical application. However, increasing studies reported that the trough level ( C 0 ) of MPA showed a poor correlation with the MPA-AUC 0-12 h ( Mathew et al, 2010 ; Barraclough et al, 2012a ; Chaabane et al, 2013 ; Cai et al, 2015 ). Owing to the requirement for frequent blood sampling, full MPA-AUC 0-12 h monitoring is laborious.…”

Therapeutic drug monitoring of enteric-coated mycophenolate sodium by limited sampling strategies is associated with a high rate of failure

“…A later time, 6 h (C 6 ), was selected to assess enterohepatic MPA cycling. AUC values were computed by the trapezoidal rule developed in our centre in 2005 according to Hale et al 's publication in kidney transplant recipients [ 21 , 22 ]. Internal validation consistently demonstrated that trapezoidal rule was equivalent to several published equations derived from linear regression and was validated by full 12-h AUC measurements that were performed in kidney transplant recipients ( n = 8, unpublished data).…”

Limited Sampling Strategy of Partial Area Under the Concentration–Time Curves to Estimate Midazolam Systemic Clearance for Cytochrome P450 3A Phenotyping

“…This method alleviates the cost and inconvenience of intense sampling, while maintaining acceptable precision and minimal bias. Limited sampling strategy has been adopted for clinical use for cyclosporine 6 , tacrolimus 7 , and mycophenolic acid 8 . With regards to IV midazolam, several limited sampling strategies have been examined.…”