Martin Šíma

Aim: This study aimed to develop a population pharmacokinetic (PK) model of intravenous fluconazole and, using model-based simulations, propose initial dosing recommendations that optimize efficacy while limiting toxicity. Methods: Therapeutic drug monitoring data from 116 adult patients (183 serum concentrations) treated with intravenous fluconazole between 2022 and 2025 at a single center were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were applied to identify dosing strategies that maximize the probability of achieving the PK/PD efficacy target. Results: Estimated glomerular filtration rate (eGFR) was the strongest predictor of fluconazole clearance, and adjusted body weight (ABW) influenced the volume of distribution. For a patient with ABW of 75 kg and eGFR of 90 mL/min, the estimated volume of distribution and clearance were 41.6 L and 0.81 L/h, respectively. An eGFR-based dosing nomogram was developed, and simulations demonstrated that this approach outperformed standard dosing regimens in achieving the PK/PD target. Conclusions: These findings suggest an initial loading dose (2.8 times the maintenance dose) followed by individualized, eGFR-guided maintenance dosing to enhance the safety and efficacy of intravenous fluconazole therapy; however, prospective clinical validation is required before routine clinical implementation.

Aims: Pharmacokinetic data for levobupivacaine in neonates are limited and largely extrapolated from older infants. We aimed to characterise population pharmacokinetics of total and unbound levobupivacaine during prolonged continuous epidural infusion in neonates and to explore determinants of protein binding and systemic exposure. Methods: In this prospective study conducted across two centres, An initial dose of levobupivacaine (1.25 mg.kg-1) followed by epidural infusion (0.2 mg.kg-1.h-1) was administered to 15 neonates. Serial plasma samples were collected up to 144 h. Total and unbound concentrations were analysed using nonlinear mixed-effects modelling. Model evaluation included goodness-of-fit plots, visual predictive checks and bootstrap analysis. Monte Carlo simulations assessed exposure and accumulation. Results: A one-compartment model best characterised levobupivacaine pharmacokinetics. The estimated typical values of clearance and volume of distribution were 0.47 L.h-1 (R.S.E. 22.7%) and 7.21 L (R.S.E. 20.0%), respectively. Protein binding was high (median 99.3%) with low variability and was influenced by developmental factors including postmenstrual age and body weight. Total concentrations showed substantial variability and occasionally reached potentially high values; however, unbound concentrations remained low. The correlation between total and unbound concentrations was weak. Simulations indicated limited accumulation. Conclusions: This study provides population pharmacokinetic data for total and unbound levobupivacaine in neonates during prolonged epidural infusion. High protein binding and a weak relationship between total and unbound concentrations suggest that unbound concentrations may better reflect systemic exposure. These findings may support improved interpretation of levobupivacaine concentrations and contribute to more informed assessment of systemic exposure during prolonged epidural analgesia in neonates.

Ibuprofen is the most commonly used NSAID; however, its short biological half‐life, reflected in the short duration of pain relief, limits the comfortableness of its usage. This study evaluated the pharmacokinetic properties of a newly developed biphasic ibuprofen 400 mg immediate‐release/sustained‐release (IR/SR) modified‐release tablets (test formulation), which was developed with an aim to overcome a need for frequent dosing. Both single‐dose and multiple‐dose, open‐label, randomized, crossover studies compared the bioavailability of the test formulation with two Nurofen 200 mg, immediate‐release coated tablets (reference formulation) administered within 4 h intervals. In addition, the effect of food on the test formulation performance was evaluated in a single‐dose, open‐label, randomized, crossover, bioavailability study. Based on the 95% confidence intervals of the geometric mean ratios, the new test formulation exhibited equivalent (80.00–125.00%) total (AUC _t,ss ), peak (C _max,ss ), and minimum (C _min,ss ) steady‐state exposure compared to the reference product after repeated dosing. After a single dose of the test formulation, total (AUC _t and AUC _∞ ) and peak (C _max0‐4 ) exposure were bioequivalent to the reference. Food intake did not significantly alter the rate or extent of drug absorption from this product. The study medication was well‐tolerated. This ibuprofen test formulation may represent a potentially advantageous therapeutic alternative, providing extended relief of mild to moderate pain. While these considerations are supported by pharmacokinetic data, further clinical evaluation may help to better characterize their relevance in practice. The formulation may be particularly suitable for conditions where less frequent dosing is desirable, such as dental and back pain, or nighttime pain.

Background: Rheumatoid arthritis is a chronic autoimmune disease characterized by synovial inflammation, cytokine imbalance, and progressive joint destruction. The endocannabinoid system has emerged as a potential therapeutic target; however, the anti-inflammatory mechanisms of non-psychoactive cannabinoids such as cannabichromene (CBC) remain insufficiently defined. This study aimed to evaluate the anti-inflammatory effects of CBC in vitro and in a collagen-induced arthritis (CIA) rat model, with a focus on key inflammatory signaling pathways. Methods: CBC effects were assessed in LPS-stimulated HUVEC cells by qPCR analysis of inflammatory markers. In vivo, female Wistar rats were assigned to four groups: CIA + saline (placebo), CIA + CBC, CIA + methylprednisolone, and non-immunized controls receiving saline. Disease progression was evaluated using clinical scoring, paw thickness, and body weight. Synovial tissues and serum were analyzed by qPCR, Western blotting, and ELISA to assess cytokines, inflammasome components, and signaling pathways, including NF-κB and JAK/STAT. Results: CBC reduced TNF-α expression in vitro at low micromolar concentrations. In vivo, CBC significantly decreased arthritis scores compared to placebo and attenuated weight loss, although it did not significantly reduce paw swelling. Molecular analyses revealed downregulation of IL-6, STAT3, and IL-17 A, indicating suppression of the TNF–NF-κB–IL-6–STAT3–Th17 axis. CBC also significantly inhibited inflammasome components (NLRP3, NLRP1A, caspase-11). However, MMP-3 and MMP-9 levels were not significantly affected. Conclusions: CBC exhibits significant anti-inflammatory activity in vitro and in vivo by modulating key cytokine and inflammasome pathways. While its effects on structural joint damage markers were limited, CBC represents a promising candidate for inflammatory arthritis therapy, warranting further investigation.

Vancomycin is a key component of empirical therapy for central nervous system (CNS) infections, yet dosing is guided by systemic pharmacokinetic/pharmacodynamic (PK/PD) targets that may not reflect drug exposure at the site of infection. Cerebrospinal fluid (CSF) penetration is variable, and the relationship between serum and CSF concentrations remains poorly defined. This study aimed to develop a population pharmacokinetic model simultaneously describing vancomycin concentrations in serum and CSF using real-world therapeutic drug monitoring (TDM) data and to characterize the relationship between systemic and CSF exposure. A retrospective observational study was conducted in adult neurosurgical patients ( n = 64) with secondary meningitis. Vancomycin concentrations in serum ( n = 133) and CSF ( n = 100) were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were performed to evaluate exposure across dosing regimens and renal function strata. Additional simulations under targeted serum exposure (AUC ₂₄ ~500 mg·h/L) with minimized interindividual variability in clearance were used to isolate variability in CSF exposure. A two-compartment model with a CSF compartment adequately described the data. Clearance was significantly associated with the estimated glomerular filtration rate. The median CSF-to-serum AUC ratio was 0.29, with substantial interindividual variability. Simulations demonstrated that, despite consistent serum exposure, CSF concentrations remained highly variable, with median (5 ^th -95 ^th percentile) average CSF concentrations of 6.2 (3.2–10.4) mg/L. The probability of achieving higher CSF concentration thresholds declined markedly with increasing targets. Vancomycin CSF exposure exhibits substantial variability that is not reliably predicted by serum pharmacokinetics, even under standardized systemic exposure. These findings highlight limitations of serum-guided dosing for CNS infections and support the need for compartment-specific dosing strategies and PK/PD targets.

Current recommendations for daptomycin dosing are based on body weight. However, it can be hypothesized that dosing based on renal function may improve the attainment of recommended pharmacokinetic (PK)/pharmacodynamic (PD) targets. The aim of this study was to develop a population pharmacokinetic model of daptomycin and propose an individualized dosing strategy to optimize target attainment. Therapeutic drug monitoring data from adult patients treated with daptomycin at a single center between 2022 and 2025 were analyzed using a nonlinear mixed-effects modeling. Monte Carlo simulations were then employed to identify the optimal dosing strategy that maximizes the probability of attaining the PK/PD target. A total of 143 daptomycin serum concentrations from 31 patients were included in the analysis. Estimated glomerular filtration rate (eGFR) was identified as the most predictive covariate for daptomycin pharmacokinetics. In a patient with an eGFR of 90 mL/min, the estimated volume of distribution and clearance of daptomycin were 11.47 L and 0.69 L/h, respectively. An eGFR-guided dosing nomogram was proposed, and simulation results demonstrated that this approach outperformed conventional weight-based dosing in achieving the PK/PD target. These findings support the use of an initial loading dose and individualized maintenance dosing based on eGFR to improve the efficacy and safety of daptomycin therapy.

Lymphatic transport of drugs after oral administration is an important physiological process in highly lipophilic compounds, such as cannabidiol (CBD). The majority of lymphatic transport studies have been historically conducted in anesthetized rats. However, this animal model differs significantly from the humans regarding both anatomical and physiological features. The aim of this study was therefore to develop a novel animal model using pigs and to provide an interspecies comparison for the lymphatic transport of CBD. The thoracic lymph duct was cannulated via thoracotomy in three pigs and lymph and blood were sampled from conscious animals to assess the lymphatic transport parameters and basic pharmacokinetic parameters of CBD administered in two distinct drug formulations (sesame oil-based solution and nanoemulsion) using a two-period cross-over study design. The mean ± SD oral bioavailability (F) was 6.1 ± 0.9% for the oil solution and 9.2 ± 6.6% for the nanoemulsion. The relative bioavailability via lymph (F_RL), i.e. the percentage of the systemically available drug that has been transported through the mesenteric lymph, was 20 ± 10% and 11 ± 13%, respectively. Whereas the F_RL for the oil solution was 2.3-fold lower in pigs compared to rats, the F_RL for the nanoemulsion was almost identical for both species. In conclusion, the lymphatic transport of CBD plays an important role after its oral administration. The particular parameters differed significantly between the rodent and higher non-rodent species. The use of higher species models is therefore warranted for the lymphatic transport assessment in settings close to humans.

Objectives: This study aims to assess the anti-inflammatory properties of cannabigerol (CBG) in collagen-induced arthritis (CIA) model in rats, and to determine which inflammatory signaling pathways it affects. Study design: Rats were randomized into four groups: placebo (PCB)–p.o. Treated with 1 mL of 0.9% saline once daily, CBG–p.o. Treated with 30 mg of CBG/day, glucocorticoids (GC)–p.o. Treated with methylprednisolone 0.5 mg/kg/day, and negative control (CO)–p.o. Treated with 1 mL of 0.9% saline once daily. CIA was induced in the PCB, GC, and CBG groups. The effect of CBG was assessed by clinical scoring, paw width measurements, ELISA, and analysis of gene (qPCR) and protein (Western blot) expression of selected inflammatory markers in blood and synovial membrane. Results: Clinical scores showed significant improvement in the CBG vs. PCB on day 29 and in the GC vs. PCB on days 24, 27, and 29. MMP-3 levels in serum were significantly reduced in the GC vs. PCB. CBG demonstrated a selective anti-inflammatory and immunomodulatory profile, notably through the downregulation of key signaling molecules such as TLRs, systemic NF-κB p65, STAT-3, and inflammasome-related components including NLRP1A, NLRP3, AIM2, gasdermin D, and caspase-1. It also reduced IL-1β and TNF expression during the early phase of disease and increased expression of the anti-apoptotic gene BCL-2. Conclusion: Our findings indicate that CBG modulates distinct components of the inflammatory signaling pathways, and its effects translated into significant improvement in clinical scoring based on swelling, erythema, stiffness in rat CIA model.