Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C₀/D) over 6–12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C₀/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C₀/D over 6–12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C₀/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C₀/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.

Previously, we performed population pharmacokinetic analysis and indicated age, mycophenolate mofetil (MMF)/mycophenolic acid (MPA) daily dose, and presence of nifedipine in patient therapy as sign...

Background/Objectives: Mycophenolic acid (MPA) is used as part of first-line combination immunosuppressive therapy for renal transplant recipients. Personalized dosing approaches are needed to balance efficacy and minimize toxicity due to the pharmacokinetic variability of the drug. In this study, population pharmacokinetic (PopPK) modeling and machine learning (ML) techniques are coupled to provide valuable insights into optimizing MPA therapy. Methods: Using data from 76 renal transplant patients, two PopPK models were developed to describe and predict MPA levels for two different formulations (enteric-coated mycophenolate sodium and mycophenolate mofetil). Covariate effects on drug clearance were assessed, and Monte Carlo simulations were used to evaluate exposure under normal and reduced clearance conditions. ML techniques, including principal component analysis (PCA) and ensemble tree models (bagging and boosting), were applied to identify predictive factors and explore associations between MPA plasma/saliva concentrations and the examined covariates. Results: Total daily dose and post-transplant time (PTP) were identified as key covariates affecting clearance. PCA highlighted MPA dose as the primary determinant of plasma levels, with urea and PTP also playing significant roles. Boosted tree analysis confirmed these findings, demonstrating strong predictive accuracy (R² > 0.91). Incorporating saliva MPA levels improved predictive performance, suggesting that saliva may be a complementary monitoring tool, although plasma monitoring remained superior. Simulations allowed exploring potential dosing adjustments for patients with reduced clearance. Conclusions: This study demonstrates the potential of integrating machine learning with population pharmacokinetic modeling to improve the understanding of MPA variability and support individualized dosing strategies in renal transplant recipients. The developed PopPK/ML models provide a methodological foundation for future research toward more personalized immunosuppressive therapy.

The results of the previous studies demonstrated an association between mycophenolic acid (MPA) exposure, serum albumin level (ALB), and adverse effects in kidney transplant patients. The aim was the identification of mathematical correlation and association between both, total and unbound MPA concentration in relation to ALB, body mass (BM), age and estimated glomerular filtration rate (eGFR) in stable kidney transplant recipients. Furthermore, investigation was conducted with the aim to clarify the role of salivary concentration (C_SAL) of MPA in adverse effect profile. In order to analyze the association between total and salivary concentration of MPA in relation to ALB, BM, age and eGFR, a least squares method for determining the correlation between these parameters was performed. In addition, derived mathematical model based on experimental data can also be performed and simulated through the Monte Carlo (MC) approach. Adverse effects were grouped according to the nature of symptoms and scored by a previously published validated system. Numerically calculated values of C_SAL from the models [C_SAL = f(ALB, BM, age, eGFR, C_P) = a₀₀ + a₁₀*(ALB, BM, age, eGFR) + a₀₁*C_P] were then compared with those from validation set of patients, where the best fitting model was for ALB [C_SAL = 54.96–1.64*ALB +13.4*C_P]. Adverse effects estimation showed the difference in esthetic score, positively correlated with C_SAL in the lower ALB group (145.41 ± 219.02 vs. 354.08 ± 262.19; with statistical significance p = .014) and almost significant for gastrointestinal score (167.69 ± 174.79 vs. 347.55 ± 320.95; p = .247). The study showed that C_SAL MPA may contribute to management of adverse effects, but these findings require confirmation of clinical utility.

Despite many health benefits to infants, the overall breastfeeding rate remains low among Serbian women. The community pharmacists’ efforts aimed at supporting nursing mothers are important. The aim of the study was an evaluation of the pharmacists’ training for breastfeeding support and their perception about its usefulness. The second aim was an evaluation of the provided structured pharmaceutical care service (SPS) over four months, through a calculation of theoretical cost savings for counseled families in case of the risk for introduction of commercial milk formula (CMF). The continuation of breastfeeding instead of starting with CMF was theoretically monetized through cost savings analysis, which is based on energy equivalent human milk and CMF, regardless of the differences in health, social and ecology outcomes of breastfeeding. Cost savings for the counseled families were calculated as financial differences between continuing breastfeeding and switching to CMF. The 256 pharmacists showed high satisfaction rates with the quality and the usefulness of the training (mean scores: content value 4.89 ± 0.51, technical value 4.91 ± 0.41, program value 4.96 ± 0.20, and usefulness value 4.94 ± 0.25, respectively), as well as a statistically significant higher level of knowledge (p < 0.001 for each of the 10 questions). The prospective observational study enrolled 256 community pharmacists who voluntarily underwent training aimed to breastfeeding support. Of all the trained pharmacists, 151 (59%) actively provided 1,243 SPS focused on breastfeeding support. Of all, 599 mothers of children under 6 months of age received SPS, while 590 provided full data In 275 cases (22.1%), a risk for early breastfeeding cessation was identified. The average age of children whose mothers had undergone SPS was 2.83 months, and the total average potential cost savings until 6 months of children age was 35,884.80 RSD (approximately 306 EUR) for average of 3.17 months. The training of pharmacists adds significant value to their knowledge and skills for breastfeeding support, which may lead to potential cost savings for families.