Nonstationary Pharmacokinetics of Caspofungin in ICU Patients.

Standard dosing of caspofungin in critically ill patients has been reported to result in lower drug exposure, which can lead to subtherapeutic 24-h area under the curve to MIC (AUC0-24/MIC) ratios. The aim of the study was to investigate the population pharmacokinetics of caspofungin in a cohort of 30 intensive care unit patients with a suspected invasive fungal infection, with a large proportion of patients requiring extracorporeal therapies, including extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). Caspofungin was administered as empirical 70 mg antifungal therapy administered intravenously (i.v.) on the first day and at 50 mg i.v. on the consecutive days once daily, and the concentrations were measured after three subsequent doses. Population pharmacokinetic data were analyzed by nonlinear mixed-effects modeling. The pharmacokinetics of caspofungin was described by two-compartment model. A particular drift of the individual clearance (CL) and the volume of distribution of the central compartment (V1) with time was discovered and described by including three separate typical values of CL and V1 in the final model. The typical CL values at days 1, 2, and 3 were 0.563 liters/h (6.7% relative standard error [6.7%RSE]), 0.737 liters/h (6.1%RSE), and 1.01 liters/h (9.1%RSE), respectively. The change in parameters with time was not explained by any of the recorded covariates. Increasing clearance with subsequent doses was associated with a clinically relevant decrease in caspofungin exposure (>20%). The use of ECMO, CRRT, albumin concentration, and other covariates did not significantly affect caspofungin pharmacokinetics. Additional pharmacokinetic studies are urgently required to assess the possible lack of acquiring steady-state and suboptimal concentrations of the drug in critically ill patients. (This study has been registered at ClinicalTrials.gov under identifier NCT03399032.).

Population analysis to assess the influence of age and body weight on pharmacokinetics and pharmacodynamics of dexmedetomidine in New Zealand White rabbits.

The purpose of this work was i) to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model of dexmedetomidine (DEX) in New Zealand White rabbits, ii) to investigate the influence of the age and weight of the animals on the model parameters, and iii) to assess the linearity of DEX PKs in the examined dose range. This was a prospective, crossover study, using a total of 18 New Zealand White rabbits. DEX was administered as a single intravenous bolus injection in the doses from 25 to 300 µg kg-1 . Each New Zealand White rabbit was given the same dose of drug in its three developmental stages. To determine the DEX PK, seven blood samples were taken from each animal. The pedal withdrawal reflex was the PD response used to assess the degree of sedation. Nonlinear mixed effects modelling was used for the population PK/PD analysis. The typical value of elimination clearance was 0.061 L min-1 and was 35% higher in younger New Zealand White rabbits compared with older animals. The PK of DEX was linear in the examined concentration range. Age-related changes in sensitivity to DEX were not detected. The results suggest that due to the pharmacokinetics, younger animals will have lower DEX concentrations and a shorter duration of sedation than older animals given the same doses of DEX per kg of body weight.

Determination of tocopherols and tocotrienols in human breast adipose tissue with the use of high performance liquid chromatography-fluorescence detection.

Tocopherols and tocotrienols have been extensively studied owing to their anticancer potential, especially against breast cancer. Therefore, the aim of this study was to quantitatively determine tocochromanols in human breast adipose tissue with the use of HPLC-FLD. The sample preparation procedure included homogenization and solvent extraction with isopropanol-ethanol-0.1% formic acid mixture prior to solid-phase extraction. After implementation of central composite design, satisfactory separation of all eight target compounds was achieved within 10.5 min. Chromatographic runs were carried out with the use of a naphthylethyl chromatographic column with methanol-water mixture (89:11, v/v) as the mobile phase. Fluorescence detection of tocochromanols was performed with excitation and emission wavelengths 298 and 330 nm, respectively. The method was validated in terms of linearity, carryover, recovery, precision, accuracy and stability. Extraction yield was also determined for accurate evaluation of vitamin E content in human breast adipose tissue samples. Finally, concentrations of particular tocochromanols compounds were assessed in human breast adipose tissue samples obtained from 99 patients, including women with breast cancer, healthy volunteers and deceased women who had died as a result of accidents. The raw data was transformed according to the newly developed equation for accurate estimation of the concentrations of tocochromanols in breast adipose tissue samples. Results obtained in the study indicated that the proposed analytical assay could be useful in breast cancer research.

Ionization of tocopherols and tocotrienols in atmospheric pressure chemical ionization.

RATIONALE: Tocopherols and tocotrienols are chemical compounds insusceptible to the ionization process under atmospheric pressure conditions. Therefore, the selection of the optimal ion source settings for their quantification requires special attention. The aim of this study was to analyse the influence of the APCI source parameters on the response of tocochromanols and two related compounds. METHODS: Standard solutions of target compounds were injected on the high-performance liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry (HPLC/APCI-MS/MS) system separately and analysed with 30 randomly selected ion source settings. The obtained responses were modelled by multivariate linear regression with least absolute shrinkage and selection operator. The developed models were used to choose the best APCI conditions. RESULTS: Multivariate linear models were built for eight tocochromanols, trolox and BHT. The APCI settings derived from the models did not increase the peak areas obtained for T and T3 during the ionization process. Ionization conditions based on models for trolox and BHT improved analytical responses by 12-36% and 4-32%, respectively. The application of the ion source settings optimal for trolox and BHT to tocochromanols did not result in better analytical responses. CONCLUSIONS: The ionization pattern of tocochromanols in the APCI source is problematic and should be further investigated. Modelling methodology for response improvement presented in this study can be applied in similar studies.

Population Pharmacokinetics of High-Dose Tigecycline in Patients with Sepsis or Septic Shock.

Tigecycline is a glycylcycline often used in critically ill patients as the antibiotic of last resort. The pharmacokinetics (PK) of tigecycline in intensive care unit (ICU) patients can be affected by severe pathophysiological changes so that standard dosing might not be adequate. The aim of this study was to describe population PK of high-dose tigecycline in patients with sepsis or septic shock and evaluate the relationship between individual PK parameters and patient covariates. The study population consisted of 37 adult ICU patients receiving a 200-mg loading dose of tigecycline followed by multiple doses of 100 mg every 12 h. Blood samples were collected at 0.5, 2, 4, 8, and 12 h after dose administration. A two-compartment model with interindividual (IIV) and interoccasion (IOV) variability in PK parameters was used to describe the concentration-time course of tigecycline. The estimated values of mean population PK parameters were 22.1 liters/h and 69.4 liters/h for elimination and intercompartmental clearance, respectively, and 162 liters and 87.9 liters for volume of the central and peripheral compartment, respectively. The IIV and IOV in clearance were less than 20%. The estimated values of distribution volumes were different from previously published values, which might be due to pathophysiological changes in ICU patients. No systematic relationship between individual PK parameters and patient covariates was found. The developed model does not show evidence that individual tigecycline dosing adjustment based on patient covariates is necessary to obtain the same target concentration in patients with sepsis or septic shock. Dosing adjustments should be based on the pathogens, their susceptibility, and PK targets.

HPLC-APCI-MS/MS method development and validation for determination of tocotrienols in human breast adipose tissue.

For the last decade, significant attention has been paid to the potential role of tocotrienols in prevention and therapy of breast cancer. Therefore, the aim of this study was to develop and validate analytical method for quantitative determination of tocotrienols (α-, ß-, γ- and δ-tocotrienol) in human breast adipose tissue with the use of high performance liquid chromatography coupled with APCI-MS/MS detection. Separation of target compounds was achieved within 10min with the use of naphthylethyl Cosmosil 2.5π-NAP column with methanol/water mixture (90:10, v/v) under isocratic elution. Adipose tissue samples were obtained from breast cancer patients and women deceased as a result of accidents. Sample preparation procedure was optimized with the application of the Plackett-Burman design and included tissue homogenization with the use of isopropanol/ethanol/aqueous 0.1% FA mixture (13:3:8, v/v), centrifugation and solid phase extraction (SPE). The method was validated in terms of linearity, precision, accuracy, stability (bench top, autosampler, postpreparative, freeze and thaw stability), matrix effect (ME), recovery (RE) and process efficiency (PE). As for all four tocotrienols ME was negligible (< 15%), precision and accuracy tests were performed with the use of tocotrienols' standard solutions within the ranges of 10.0-400.0ng/g for all four tocotrienols. As the validation requirements were met, the validated method was applied for quantitative analysis of tocotrienols in breast cancer patients.