Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients

Abstract

Purpose: The dose of mycophenolate mofetil (MMF) used to prevent rejection after lung transplantation is often adjusted based on the 12-hour area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). A limited sampling strategy (LSS) is useful to define the pharmacokinetic (PK) profiles of MPA and mycophenolic acid acyl glucuronide (AcMPAG). Therefore, this study aimed to design a LSS based on multiple linear regression for estimating the AUC0-12 of MPA and AcMPAG at the minimum blood sampling points in Japanese lung transplant patients with concomitant tacrolimus. Methods: Forty-five lung transplantation recipients were enrolled in a PK study of MPA, mycophenolic acid glucuronide (MPAG), and AcMPAG. The plasma MPA, MPAG, and AcMPAG concentrations were determined just before and at 0.5, 1, 2, 4, 8, and 12 hours after dosing. The AUC0-12 of MPA and AcMPAG was calculated using a linear trapezoidal rule from the plasma concentration of each blood sampling time. LSS was used to develop models for estimated AUC in the model group (n = 23) and was evaluated in the validation group (n = 22). Results: The best three time-point equation was 4.04 + 1.64·C1 + 3.08·C4 + 5.17·C8 for MPA, and -0.13 + 3.01·C1 + 3.51·C4 + 5.74·C8 for AcMPAG. The prediction errors (PE) and the absolute prediction errors (APE) were within the clinically acceptable ± 5% and 15% range, respectively (MPA: PE = 2.00%, APE = 11.66%, AcMPAG: PE = 0.98%, APE = 14.69%). The percentage of estimated AUC0-12 within ± 15% of the observed AUC0-12 was 77.27% for MPA and 81.82% for AcMPAG. Conclusion: LSS using three time-point (C1, C4, and C8) provides the most reliable and accurate simultaneous estimation of the AUC0-12 of MPA and AcMPAG in Japanese lung transplant patients.

A Systematic Review of Multiple Linear Regression-Based Limited Sampling Strategies for Mycophenolic Acid Area Under the Concentration–Time Curve Estimation

“…Among other MMF indications in adults than rejection prophylaxis after renal transplantation, studies aiming at establishing LSS for liver transplant recipients ( n = 5) [ 51 , 54 , 57 , 58 , 60 ], heart transplant recipients ( n = 5) [ 52 , 55 , 56 , 62 , 70 ], lung transplant recipients ( n = 2) [ 50 , 59 ], and hematopoietic stem cell transplant recipients ( n = 2) [ 49 , 61 ] were found. There were single studies including patients after islet transplantation [ 20 ], patients with autoimmune diseases (antineutrophil cytoplasmic antibody-associated systemic vasculitis and systemic lupus erythematosus) [ 53 ] and patients with anti-neutrophil cytoplasmic antibody-associated vasculitis [ 71 ] (Table 2 ).…”

“…The most frequent limitation was a relatively small sample size [ 20 , 26 , 31 , 32 , 36 , 41 , 43 , 45 , 48 , 49 , 56 , 70 , 71 ]. The duration of MMF treatment was a limitation and concerned the substantial difference in the duration of treatment and regimens among patients [ 49 , 64 ], late post-transplant period (approximately 4 years) [ 50 ] or narrow time range to the first two post-transplant weeks [ 70 ]. Some of the studies included patients of only one race in the evaluation [ 19 , 50 ] or with trace proteinuria during the day of blood collection [ 19 ], others did not fully supervise the contribution of concomitant drugs [ 16 , 19 , 26 , 64 , 71 ].…”

“…The duration of MMF treatment was a limitation and concerned the substantial difference in the duration of treatment and regimens among patients [ 49 , 64 ], late post-transplant period (approximately 4 years) [ 50 ] or narrow time range to the first two post-transplant weeks [ 70 ]. Some of the studies included patients of only one race in the evaluation [ 19 , 50 ] or with trace proteinuria during the day of blood collection [ 19 ], others did not fully supervise the contribution of concomitant drugs [ 16 , 19 , 26 , 64 , 71 ]. Several studies excluded patients with gastrointestinal disease or diarrheal illness [ 32 ] or those with rejection or notable adverse effects [ 20 , 41 ].…”

“…Several studies excluded patients with gastrointestinal disease or diarrheal illness [ 32 ] or those with rejection or notable adverse effects [ 20 , 41 ]. Few limitations concerned the pharmacokinetics, such as MPA LSS overprediction of AUC by 30% [ 61 ], low frequency of the sample collection at time intervals [ 19 , 50 ], and the exclusion from the dataset of profiles with either extraordinarily high MPA C 0 or delayed absorption ( t max > 2 h) [ 36 ]. In one study, the lack of control patients was emphasized [ 64 ].…”

Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation

“…No evidence has confirmed this formula to fit our cohort consisting mostly of adult lung transplant recipients. To our best knowledge, a calculation formula for MPA AUC specific for lung transplant recipients was recently reported, 29 and this formula required the concentration levels at 1, 4, and 8 hours after intake. Those levels were not available in the present study, and therefore, another calculation formula was utilized for this study.…”