Heart Transplant Patients in a wide population observed for Mycophenolic Acid Area Under The Curve executed with a limited sampling strategy technique

Aim The study aim is the validation of two algorithms of Limited Sampling Strategy (LSS) for the quantification of Mycophenolic Acid (MPA) Area under the plasma concentration-time curve from 0 to 12h (AUC0-12h) in a cohort of non-selected Heart Transplant (HTx) recipients treated, as standard clinical practice, with Mycophenolate Mofetil (MMF) combined with Cyclosporine (CsA), or Tacrolimus (TAC). These two LSSs were previously tested and validated by Baraldo et al. in a cohort of selected HTx recipients 1,2. The value of MPA AUC0-12h (real and estimated with LSSs) among non-rejected (NR) and rejected (R) patients were evaluated. Methods Linear regression and Bland Altman Analysis validated two LSSs methods (named LSS3 and LSS4 by number of blood samples used). The value of MPA AUC0-12h between NR and R patients were compared by Mann-Whitney test. Results The validation reports positive results for LSS3 and LSS4 according to linear regression (r=0.91 and 0.94 and R2=0.84 and 0.88, respectively) and Bland Altman Analysis (p=0.04 and 0.04). There was a difference of borderline statistically significance (p=0.06) for the median value of MPA AUC0-12h (mg×h/L) between NR and R patients (46.60; Interquartile Range (IQR): 34.80-64.10 vs 33.70; IQR: 23.60-48.25); whereas the difference was statistically significant for both LSS3 and LSS4 (p=0.03 and 0.04). Conclusion The capability of these two LSSs to estimate MPA AUC0-12h in cohort of non-selected HTx recipients and the suggestion of a significant difference on MPA AUC0-12h between NR and R patients, confirm the importance of MPA quantification in the clinical field.

Limited Sampling Strategy for Estimation of Mycophenolic Acid Exposure in Adult Chinese Heart Transplant Recipients

Background: With the increasing use of mycophenolic acid (MPA) formulations in organ transplantation, the need for personalized immunosuppressive therapy has become well recognized based on therapeutic drug monitoring (TDM) for avoidance of drug-related toxicity while maintaining efficacy. Few studies have assessed area under the 12 h concentration-time curve of MPA (MPA-AUC0–12h) in heart transplant recipients who received mycophenolate mofetil (MMF) dispersible tablets (MMFdt). The aim of the study was to investigate the pharmacokinetics (PK) of MMFdt combined with tacrolimus and further to develop a practical method for estimation of MPA-AUC0–12h using a limited sampling strategy (LSS).Methods: A prospective study in a single center was performed in patients who continuously administrated with MMFdt or MMF capsule (MMFc) for at least 7 days after cardiac transplantation from 2018 to 2020. A total of 48 Chinese adult heart transplant recipients were enrolled. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after MMF administration. The validated high-performance liquid chromatography combined with tandem mass spectrometry method was used to measure MPA concentrations. Non-compartmental pharmacokinetic (PK) analysis was applied to calculate the data obtained from individual recipients by WinNonlin. LSS models were developed for MPA-AUC0–12h prediction with multivariate stepwise regression analysis.Results: A large inter-individual variability was observed in AUC0–12h, Tmax, Cmax, MRT0–12h, t1/2 and CL/F after multiple dosing of MMFdt. However, no significant differences were observed between main PK parameters of MMFdt and MMFc. The best estimation of MPA-AUC0–12h was achieved with four points: MPA-AUC0–12h = 8.424 + 0.781 × C0.5 + 1.263 × C2 + 1.660 × C4 + 3.022 × C6 (R2 = 0.844). The mean prediction error (MPE) and mean absolute prediction error (MAPE) of MPA-AUC0–12h were 2.09 ± 14.05% and 11.17 ± 8.52%, respectively. Both internal and external validations showed good applicability for four-point LSS equation.Conclusion: The results provide strong evidence for the use of LSS model other than a single time-point concentration of MPA when performing TDM. A four-point LSS equation using the concentrations at 0.5, 2, 4, 6 h is recommended to estimate MPA-AUC0–12h during early period after transplantation in Chinese adult heart transplant recipients receiving MMFdt or MMFc. However, proper internal and external validations with more patients should be conducted in the future.

Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data

Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0–1–2–4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.

Two-point limited sampling strategy is necessary to estimate the area under the concentration-time curve for intravenous busulfan in infants and young children

Background: Therapeutic drug monitoring for busulfan is important to prevent adverse events and improve outcomes in stem cell transplantation. We investigated intravenous busulfan pharmacokinetics and evaluated the utility of limited sampling strategy (LSS) as a simple method to estimate the area under the concentration-time curve (AUC). Procedure: The study comprised 87 busulfan measurements in 54 children who received intravenous busulfan between August 2015 and May 2020. AUCs were calculated from 3–5 blood sampling points in each patient, and the correlation between AUC and plasma concentrations (ng/mL) at 1, 2, 3, 4, and 6 h after initiating busulfan infusion (C, C, C, C, and C, respectively). Results: By one-point sampling strategy, the most accurate predicted AUC was based on C (r = 0.789; precision, 11.0%) in all patients. The predicted AUC based on C was highly precise (r = 0.937; precision, 5.9%) in adolescent patients weighing > 23 kg, but the correlation was poor in infants and young children weighing ≤23 kg (r = 0.782; precision, 11.4%). By two-point sampling strategy, the predicted AUC based on C and C showed the most favorable performance (r = 0.943; precision, 6.4%), even in infants and young children, whereas the predicted AUC based on C and C was acceptable (r = 0.963; precision, 5.7%). Conclusions: The AUC of busulfan can be predicted based on C in adolescent patients. However, there was substantial inter-individual variation in busulfan pharmacokinetics in infants and young children, in whom two-point LSS was necessary for accurate AUC prediction.