A Limited Sampling Strategy for Therapeutic Drug Monitoring of Mycophenolate Mofetil for Prophylaxis of Acute Graft-Versus-Host Disease in Allogeneic Stem Cell Transplantation

Abstract

A universally accepted strategy for therapeutic drug monitoring (TDM) of mycophenolate mofetil (MMF) in the prevention of acute graft-versus-host disease (aGVHD) in allogenic hematopoietic stem cell transplantation (alloHSCT) does not exist. We explored the feasibility of developing a limited sampling strategy (LSS) for TDM of MMF in this setting. Patients undergoing alloHSCT received standard MMF-cyclosporine prophylaxis, with MMF administered twice daily (BD) for matched transplant recipients or thrice daily (TID) in haploidentical transplantation. Intensive blood sampling was carried out on day 7 and area under the concentration–time curve (AUC) of mycophenolic acid (MPA), the active metabolite, was estimated using noncompartmental analysis. The ability of MPA exposure defined by AUC0-12 to discriminate between responders (patients who did not develop GVHD) and nonresponders (patients who developed GVHD) was determined by receiver operating characteristic curve analysis. Patients were divided into training and validation sets within BD and TID groups. Mathematical equations were developed from the training set to predict AUC0-12 from an abbreviated AUC involving a limited number of sampling points. The equations were validated in the validation set by comparing the MPA AUC0-12 predicted from LSS with the observed AUC0-12. It was observed that patients with AUC0-12 ≤18.99 mg*h/L had a higher risk of developing aGVHD [odds ratio (OR) = 2.63 (1.17 to 5.87), P = 0.06]. The benefit was more in matched transplant recipients [OR = 3.5 (1.30 to 9.49), P = 0.05] as compared to haploindentical transplant [OR = 2.8 (0.49 to 15.91), P = NS]. Using the mathematical equations, the observed AUC0-12 was predicted with 92.31% accuracy in the BD subset and 100% accuracy in the TID subset for a combined accuracy of 94.76%. A set of just three samples that constituted the abbreviated AUC1-4 was used to develop the predictive models. The LSS could be employed for the therapeutic monitoring of MMF particularly in patients undergoing matched hematopoietic stem cell transplantation.

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 ).…”

“…In one study, separate LSSs were established after oral and intravenous MMF administration for both total and fMPA [ 61 ]. One LSS consisted of AUC 1-4 instead of particular time points [ 49 ].…”

The Evaluation of Multiple Linear Regression–Based Limited Sampling Strategies for Mycophenolic Acid in Children with Nephrotic Syndrome

“…The search of the literature returned 29 studies meeting the requirements concerning MLR LSSs for MPA and fMPA, dated 1998–2020. We applied 48 MPA LSSs [ 8 , 9 , 14 , 21 , 22 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] and five fMPA LSSs [ 35 , 36 , 42 ] found in the literature to calculate the predicted area under the (0–12 h) time–concentration curve (AUC pred ) in children with nephrotic syndrome treated with MMF, and compared the results with AUC total . In the majority of studies, calcineurin inhibitors (CsA or tacrolimus (Tac)) were co-administered with MMF.…”

“…These LSSs included C 1 -C 2 -C 4 and C 1 -C 2 -C 6 , both of which were established for Tac co-administration. High r 2 was found in the Gota et al [ 34 ] equation, concomitantly with low predictive performance. A number of 11 LSSs (48%) gave an AUC pred within ±15% of the AUC total for less than 50% of children.…”

“…Moreover, equations with only one time-point performed poorly with respect to the percentage of the AUC pred within ±15% of the AUC total (≤33%). Interestingly, for one LSS, which included AUC 1–4 instead of concentration at defined time points [ 34 ], r 2 was >0.800, while the predictive performance and the percentage of the AUC pred within ±15% of the AUC total were unsatisfactory. Moreover, the LSSs which included logarithmic concentrations did not perform well [ 44 ].…”