Radzevičienė, Aurelija
Item type:Publication, conference output[2026][T1e][M003][1]Aim: To summarize pregnancy-related physiological changes that may alter bupivacaine pharmacokinetics and identify parameters relevant to future physiologically based pharmacokinetic (PBPK) modeling and dosage optimization. Methods: A narrative review of peer-reviewed literature relevant to bupivacaine physiochemical properties, plasma protein binding, distribution, metabolism, placental transfer, pregnancy physiology, maternal toxicity, and PBPK modeling was performed. Findings were synthesized to identify consistent pharmacokinetic tendencies and knowledge gaps. Results: Pregnancy produces progressive increases in plasma volume, cardiac output, renal perfusion, and body water, while albumin and alpha-1-acid glycoprotein concentrations decrease. Because bupivacaine is highly protein bound, reduced binding may increase its unbound, pharmacologically active fraction. Concurrent changes in tissue perfusion, body composition, hepatic blood flow, and enzyme activity may alter its apparent distribution and clearance. The reviewed evidence indicates that total plasma concentration alone may underestimate biologically active exposure during pregnancy. Placental transfer and the cardiotoxic and neurotoxic potential of unbound bupivacaine further support evaluating maternal and fetal exposure separately. However, available studies are heterogenous, and pregnancy-specific dosing recommendations based on integrated pharmacokinetic evidence remain limited. Conclusions: Pregnancy may meaningfully modify bupivacaine disposition, particularly through reduced plasma protein binding and altered distribution and clearance. These findings provide a rationale for pregnancy-specific PBPK modeling to quantify trimesterdependent maternal and fetal exposure to evaluate whether current dosing approaches adequately balance analgesia and toxicity risk.
1 Item type:Publication, conference output[2026][T1e][M003][2]; Ramishvili, DavitJoint International PhD Student Conference in Biomedical Sciences : Programme and abstract book : 7 August 2026, 2026-08-07, p. 8-9Aim: To optimize MMF precision dosing using Simcyp PBPK simulations and identify dosing regimens associated with optimal therapeutic exposure. Methods: The study involved 100 healthy participants in a PBPK model who received 3 different treatment doses: 500mgx2/day, 750mgx2/day and 1000mgx2/day. Blood samples were collected twice a day during two different measurement periods based on the dosage schedule. Concentration analyses were conducted using the Simcyp simulator. The therapeutic range is established at 1 to 4 mg/L. Results: Model-based simulations identified significant differences in target therapeutic exposure among the evaluated MMF dosing regimens. The 500 mg twice-daily regimen generated MPA concentrations predominantly within the lower therapeutic range, potentially increasing the likelihood of inadequate immunosuppression. The 750 mg twice-daily regimen achieved optimal target attainment, maintaining MPA concentrations consistently within the predefined therapeutic window (1-4 mg/L) across the simulated population. In contrast, the 1000 mg twice-daily regimen resulted in systematic exceedance of the therapeutic threshold, indicating a high probability of overexposure. Overall, PBPK modeling supported 750 mg twice daily as the dosing regimen most likely to maximize therapeutic efficacy while minimizing the risks associated with under- and overexposure. Conclusions: Data from the SymCyp simulator indicates that the optimal treatment dosage is 750 mg taken twice daily for a healthy population. The 500 mg dosage taken twice daily resulted in periods when drug levels fell below 1 mg/L what may lead to insufficient immunosuppression and organ rejection, while the 1000 mg dosage taken twice daily led to all patients exceeding the therapeutic concentration range what may lead to increased risk of adverse effects.
3 4 Item type:Publication, book[2025][K2c][M003][79]; Kaunas : LSMU Akademinė leidyba, 2025-12-18Šios bendrosios farmakologijos užduotys yra skirtos III kurso farmacijos studijų krypties studentams, norintiems geriau įsisavinti farmakologijos pagrindų studijų krypties programą, ir medicinos studijų krypties studentams, norintiems pagilinti farmakologijos žinias. Pateikti klausimai ir užduotys padeda susipažinti su vaistų grupėmis, nagrinėti vaistų farmakokinetiką ir farmakodinamiką, susieti vaisto mechanizmą su panaudojimo galimybėmis ir galimomis nepageidaujamomis reakcijomis. Naudojimosi leidiniu patarimai: rekomenduojame praktines užduotis atlikti susipažinus su rekomenduojama literatūra ir papildoma literatūra, pateikta po kiekvienu skyreliu, kita per paskaitas pateikta medžiaga. Užduotys skirtos pirmiausia išsiaiškinti vaistų klasės veikimo mechanizmą ir jo pagrindu suprasti vaistų panaudojimo galimybes, pastebėti sukeliamą nepageidaujamą poveikį.
46 2 Item type:Publication, conference output[2025][T1a][N010][3]; Ramishvili, DavitBritish Journal of Clinical Pharmacology : Selected Abstracts from Pharmacology 2025, 2025-12-09, vol. 92, no. 2, Suppl., p. 748-750Background Mycophenolate mofetil (MMF) is one of the standard therapy immunosuppressant after kidney transplantation. Because of enterohepatic cycling, the second recirculation peak appears in the blood that makes it hard to optimize treatment. Optimization of the efficacy in MMF treatment to achieve better results requires a complete understanding of its pharmacokinetics and dosing techniques. Simcyp simulations with clinical data allow us to determine potential areas for enhancement in MMF therapy, in order to improve the effectiveness with minimal risk involved. The main objective is to optimize MMF treatment approaches and increase therapeutic outcomes. Methods The study involved 100 healthy participants in a PBPK model who received three different treatment dose: 500 mg 2/day, 750 mg 2/day and 1000 mgx2/day. Blood samples were collected twice a day during two different measurement periods based on the dosage schedule. Concentration analyses were conducted using the Simcyp simulator. The therapeutic range is established at 1 to 4 mg/L. Results In the group of patients taking 1 g/day, MPA levels ranged from 1 to 3.5 mg/L. Although all these patients' MPA levels were within the therapeutic range of 1–4 mg/L, they were on the lower end of that range. In contrast, patients taking 1.5 g/day had MPA levels that also ranged from 1 to 4 mg/L, with all levels staying within the therapeutic range. However, in the group taking 2 g/day, all patients' MPA levels above the therapeutic range.
36 Item type:Publication, review article[2025][S1][M001,N010][49]; International Journal of Molecular Sciences, 2025-10-10, vol. 26, no. 20, p. 1-49Antimicrobial resistance (AMR) is a growing global threat, exacerbated by the adaptive mechanisms of Gram-negative ESKAPE pathogens, which include biofilm formation and outer membrane vesicle (OMV) production. Biofilms create robust protective barriers that shield bacterial communities from immune responses and antibiotic treatments, while OMVs contribute to both defense and offense by carrying antibiotic-degrading enzymes and delivering virulence factors to host cells. These mechanisms not only enhance bacterial survival but also increase the virulence and persistence of infections, making them a significant concern in clinical settings. This review explores the molecular processes that drive biofilm and OMV formation, emphasizing their critical roles in the development of AMR. By understanding these mechanisms, new therapeutic strategies can be developed to disrupt these defenses, potentially improving the efficacy of existing antibiotics and slowing the spread of resistance. Additionally, the use of OMVs in vaccine development and drug delivery offers promising avenues for future research. Addressing these challenges requires a comprehensive approach, combining advanced research with innovative therapies to combat the escalating threat of AMR and improve patient outcomes.
24 7WOS© Citations 10 - conference paper[2025][T1e][M003][2]
Background: Mycophenolate mofetil (MMF) is one of the standard therapy immunosuppressant after kidney transplantation. Because of enterohepatic cycling, the second recirculation peak appears in the blood that makes it hard to optimize treatment. Optimization of the efficacy in MMF treatment to achieve better results requires a complete understanding of its pharmacokinetics and dosing techniques. Simcyp simulations with clinical data allow us to determine potential areas for enhancement in MMF therapy, in order to improve the effectiveness with minimal risk involved. The main objective: to optimize MMF treatment approaches and increase therapeutic outcomes. Methods: The study involved 100 healthy participants in a PBPK model who received 3 different treatment dose: 500mgx2/day, 750mgx2/day and 1000mgx2/day. Blood samples were collected twice a day during two different measurement periods based on the dosage schedule. Concentration analyses were conducted using the Simcyp simulator. The therapeutic range is established at 1 to 4 mg/L. Results: In the group of patients taking 1g/day, MPA levels ranged from 1 to 3.5 mg/L. Although all these patients' MPA levels were within the therapeutic range of 1-4 mg/L, they were on the lower end of that range. In contrast, patients taking 1.5g/day had MPA levels that also ranged from 1 to 4 mg/L, with all levels staying within the therapeutic range. However, in the group taking 2g/day, all patients’ MPA levels above the therapeutic range. Conclusion: Data from the SymCyp simulator indicates that the optimal treatment dosage is 750 mg taken twice daily for a healthy population. The 500 mg dosage taken twice daily resulted in periods when drug levels fell below 1 mg/L what may lead to insufficient immunosuppression and organ rejection, while the 1000 mg dosage taken twice daily led to all patients exceeding the therapeutic concentration range what may lead to increased risk of adverse effects.
3 Item type:Publication, research article[2025][S1][M001,N010][43]; ; ; Antibiotics (Basel, Switzerland), 2025-01-09, vol. 14, no. 1, p. 1-43Multidrug antimicrobial resistance (AMR) represents a formidable challenge in the therapy of infectious diseases, triggered by the particularly concerning gram-negative Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. (ESKAPE) pathogens. Designated as a “priority” in 2017, these bacteria continue to pose a significant threat in 2024, particularly during the worldwide SARS-CoV-2 pandemic, where coinfections with ESKAPE members contributed to worsened patient outcomes. The declining effectiveness of current treatments against these pathogens has led to an increased disease burden and an increase in mortality rates globally. This review explores the sophisticated mechanisms driving AMR in gram-negative ESKAPE bacteria, focusing on Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterobacter spp. Key bacterial mechanisms contributing to resistance include limitations in drug uptake, production of antibiotic-degrading enzymes, alterations in drug target sites, and enhanced drug efflux systems. Comprehending these pathways is vital for formulating innovative therapeutic strategies and tackling the ongoing threat posed by these resistant pathogens.
14 11WOS© Citations 48 Item type:Publication, research article[2024][S1][M001,N010][19]; Diagnostics (Basel, Switzerland), 2024-10-18, vol. 14, no. 20, p. 1-19Antimicrobial Resistance (AMR) has evolved from a mere concern into a significant global threat, with profound implications for public health, healthcare systems, and the global economy. Since the introduction of antibiotics between 1945 and 1963, their widespread and often indiscriminate use in human medicine, agriculture, and animal husbandry has led to the emergence and rapid spread of antibiotic-resistant genes. Bacteria have developed sophisticated mechanisms to evade the effects of antibiotics, including drug uptake limitation, drug degradation, target modification, efflux pumps, biofilm formation, and outer membrane vesicles production. As a result, AMR now poses a threat comparable to climate change and the COVID-19 pandemic, and projections suggest that death rates will be up to 10 million deaths annually by 2050, along with a staggering economic cost exceeding $100 trillion. Addressing AMR requires a multifaceted approach, including the development of new antibiotics, alternative therapies, and a significant shift in antibiotic usage and regulation. Enhancing global surveillance systems, increasing public awareness, and prioritizing investments in research, diagnostics, and vaccines are critical steps. By recognizing the gravity of the AMR threat and committing to collaborative action, its impact can be mitigated, and global health can be protected for future generations.
11WOS© Citations 13 Item type:Publication, journal article[2024][S1][M001,N010][14]; ; ; ; Biomedicines, 2024-05-18, vol. 12, no. 5, p. 1-14Tacrolimus (TAC) has a narrow therapeutic window and patient-specific pharmacokinetic variability. In our study, we analyzed the association between TAC exposure, metabolism, and kidney graft outcomes (function, rejection, and histological lesions). TAC trough (C), coefficient of variation (TAC CV), concentration/dose ratio (C/D), and biomarkers related to kidney injury molecule-1 (KIM-1) and neutrophil gelatinase lipocalin (NGAL) were analyzed. We examined 174 patients who were subjected to a triple immunosuppressive regimen and underwent kidney transplantation between 2017 and 2022. Surveillance biopsies were performed at the time of kidney implantation and at three and twelve months after transplantation. We classified patients based on their Tac C/D ratios, classifying them as fast (C/D ratio < 1.05 ng/mL × 1/mg) or slow (C/D ratio ≥ 1.05 ng/mL × 1/mg) metabolizers. TAC exposure/metabolism did not significantly correlate with interstitial fibrosis/tubular atrophy (IF/TA) progression during the first year after kidney transplantation. TAC CV third tertile was associated with a higher chronicity score at one-year biopsy. TAC C/D ratio at three months and Tac C at six months were associated with rejection during the first year after transplantation. A fast TAC metabolism at six months was associated with reduced kidney graft function one year (OR: 2.141, 95% CI: 1.044-4.389, = 0.038) and two years after transplantation (OR: 4.654, 95% CI: 1.197-18.097, = 0.026), and TAC CV was associated with reduced eGFR at three years. uNGAL correlated with IF/TA and chronicity scores at three months and negatively correlated with TAC C and C/D at three months and one year. Conclusion: Calculating the C/D ratio at three and six months after transplantation may help to identify patients at risk of suffering acute rejection and deterioration of graft function.
18WOS© Citations 7 Item type:Publication, journal article[2024][S1][M001,N010][15]; ; ; ; ; Diagnostics, 2024-03-28, vol. 14, no. 7, p. 1-15With an increasing number of marginal donors, additional methods for the evaluation of cadaveric kidney quality are required. This study aimed to evaluate pretransplant deceased donor serum (s) and urine (u) biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18, and C-X-C motif chemokine 10 (CXCL10) for predicting early and late graft function. In total, 43 deceased kidney donors and 76 corresponding recipients were enrolled. Delayed graft function (DGF) occurred in 27.6% of cases. sIL-18, sKIM-1, uNGAL, and uKIM-1 were predictors of DGF. A model incorporating sIL-18, uKIM-1, and clinical factors was developed to predict DGF (AUROC 0.863). Univariate analysis showed a negative association between uKIM and graft eGFR at 6, 12, 24, and 36 months, but this was not confirmed in the multivariate analysis. In conclusion, we report a superior performance of donor biomarkers for predicting DGF and later graft function over serum creatinine. Higher levels of donor sIL-18 and uKIM in conjunction with expanded-criteria donors and longer cold ischemia times predicted DGF. With no renal tubular damage in zero-time donor biopsies, higher pretransplant urine and serum NGAL levels were associated with better allograft function one year after transplantation, and sNGAL with graft function three years after transplantation.
22WOS© Citations 6