This study aimed to develop a vancomycin population pharmacokinetic model in obese adult patients treated with intermittent haemodialysis and propose a model-based loading dose strategy ensuring attainment of newly recommended AUC-based PK/PD target. Retrospective cross-sectional analysis was performed among obese haemodialysis dependent adult patients treated with intravenous vancomycin. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were used to identify the optimal loading dose for PK/PD target attainment during the first 48 h of treatment. Therapeutic drug monitoring data from 27 patients with a BMI of 30.2-52.9 kg/m2 were analysed. Among all tested variables, only LBM as a covariate of vancomycin Vd significantly improved the model, while vancomycin CL did not correlate with any of the tested variables. The median (IQR) value from the conditional mean of individual estimates of Vd and CL was 68.4 (56.6-84.2) L and 0.86 (0.79-0.90) L/h, respectively. To ensure optimal vancomycin exposure during the first 48 h of therapy, the vancomycin loading dose of 1500, 1750, 2000, 2250, 2500 and 2750 mg should be administered to obese patients with a lean body mass of ˂50, 50-60, 60-70, 70-80, 80-85 and >85 kg, respectively.

• MeSH
• antibakteriální látky * farmakokinetika   aplikace a dávkování   MeSH
• biologické modely MeSH
• dialýza ledvin * MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv MeSH
• obezita * komplikace   MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• senioři MeSH
• vankomycin * farmakokinetika   aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

AIMS: Abiraterone treatment requires regular drug intake under fasting conditions due to pronounced food effect, which may impact patient adherence. The aim of this prospective study was to evaluate adherence to abiraterone treatment in patients with prostate cancer. To achieve this aim, an abiraterone population pharmacokinetic model was developed and patients' adherence has been estimated by comparison of measured levels of abiraterone with population model-based simulations. METHODS: A total of 1469 abiraterone plasma levels from 83 healthy volunteers collected in a bioequivalence study were analysed using a nonlinear mixed-effects model. Monte Carlo simulation was used to describe the theoretical distribution of abiraterone pharmacokinetic profiles at a dose of 1000 mg once daily. Adherence of 36 prostate cancer patients treated with abiraterone was then evaluated by comparing the real abiraterone concentration measured in each patient during follow-up visit with the theoretical distribution of profiles based on simulations. Patients whose abiraterone levels were ˂5th or ˃95th percentile of the distribution of simulated profiles were considered to be non-adherent. RESULTS: Based on this evaluation, 13 patients (36%) have been classified as non-adherent. We observed significant association (P = .0361) between richness of the breakfast and rate of non-adherence. Adherent patients reported significantly better overall condition in self-assessments (P = .0384). A trend towards a higher occurrence of adverse effects in non-adherent patients was observed. CONCLUSIONS: We developed an abiraterone population pharmacokinetic model and proposed an advanced approach to medical adherence evaluation. Due to the need for administration under fasting conditions, abiraterone therapy is associated with a relatively high rate of non-adherence.

• MeSH
• adherence k farmakoterapii * statistika a číselné údaje   MeSH
• androsteny * farmakokinetika   aplikace a dávkování   terapeutické užití   MeSH
• biologické modely * MeSH
• dospělí MeSH
• interakce mezi potravou a léky MeSH
• lidé středního věku MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• nádory prostaty * farmakoterapie   MeSH
• omezení příjmu potravy MeSH
• prospektivní studie MeSH
• protinádorové látky farmakokinetika   aplikace a dávkování   MeSH
• senioři MeSH
• terapeutická ekvivalence MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

• MeSH
• biologické modely MeSH
• dospělí MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• monitorování léčiv * MeSH
• plíce MeSH
• příjemce transplantátu * MeSH
• senioři MeSH
• vorikonazol farmakokinetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

AIM: The objective of this study was to evaluate off-label high-dose ceftazidime population pharmacokinetics in cancer patients with suspected or proven extensively drug-resistant (XDR) Pseudomonas aeruginosa infections and then to compare the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target after standard and off-label high-dose regimens using population model-based simulations. A further aim was to clinically observe the occurrence of adverse effects during the off-label high-dose ceftazidime treatment. METHODS: In patients treated with off-label high-dose ceftazidime (3 g every 6 h), blood samples were collected and ceftazidime serum levels measured using LC-MS/MS. A pharmacokinetic population model was developed using a nonlinear mixed-effects modelling approach and Monte Carlo simulations were then used to compare standard and high-dose regimens for PK/PD target attainment. RESULTS: A total of 14 cancer patients with serious infection suspected of XDR P. aeruginosa aetiology were eligible for PK analysis. XDR P. aeruginosa was confirmed in 10 patients as the causative pathogen. Population ceftazidime volume of distribution was 13.23 L, while clearance started at the baseline of 1.48 L/h and increased by 0.0076 L/h with each 1 mL/min/1.73 m2 of eGFR. High-dose regimen showed significantly higher probability of target attainment (i.e., 86% vs. 56% at MIC of 32 mg/L). This was translated into a very low mortality rate of 20%. Only one case of reversible neurological impairment was observed. CONCLUSION: We proved the superiority of the ceftazidime off-label high-dose regimen in PK/PD target attainment with very low occurrence of adverse effects. The off-label high-dose regimen should be used to optimize treatment of XDR P. aeruginosa infections.

• MeSH
• antibakteriální látky škodlivé účinky   farmakokinetika   MeSH
• ceftazidim škodlivé účinky   farmakokinetika   MeSH
• chromatografie kapalinová MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• mikrobiální testy citlivosti MeSH
• nádory * komplikace   farmakoterapie   MeSH
• off-label použití léčivého přípravku MeSH
• pseudomonádové infekce * farmakoterapie   MeSH
• Pseudomonas aeruginosa MeSH
• tandemová hmotnostní spektrometrie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIMS: The aim of this pharmacokinetic study was to describe and quantify population pharmacokinetics of three antibiotics, cefazolin, ampicillin, and ciprofloxacin, used as antibacterial prophylaxis during cardiovascular surgery with the use of extracorporeal circulation (ECC). METHODS: Adult patients undergoing cardiac surgery with ECC were enrolled to this prospective, pharmacokinetic study. An intravenous bolus of 2 g of ampicillin, 2 g of cefazolin or 400 mg of ciprofloxacin was administered 60-30 min before surgery. Blood samples were collected at 15, 30, 45, 60, 120 and 180 min after the administration and at the end of the surgery. Plasma concentrations of the antibiotics were measured using HPLC methods. Serum concentration-time profiles were analyzed using nonlinear mixed-effects modeling approach. RESULTS: A total of 54 patients were enrolled into the study, 20 with ampicillin, 25 cefazolin and 9 ciprofloxacin. For all antibiotics, population pharmacokinetic models have been successfully developed. CONCLUSION: We identified estimated glomerular filtration rate (eGFR) as the main factor determining the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) target in ampicillin or cefazolin and body weight in ciprofloxacin prophylaxis during cardiac surgery with ECC support.

• MeSH
• ampicilin MeSH
• antibakteriální látky terapeutické užití   MeSH
• antibiotická profylaxe metody   MeSH
• cefazolin * farmakokinetika   terapeutické užití   MeSH
• ciprofloxacin MeSH
• dospělí MeSH
• kardiochirurgické výkony * MeSH
• lidé MeSH
• mimotělní oběh MeSH
• prospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The aim of this study was to describe and quantify pharmacokinetics of ampicillin used prophylactically in cardiac surgery both with and without cardiopulmonary bypass (CPB) using population pharmacokinetic analysis in order to propose an optimal dosing strategy. Adult patients undergoing cardiac surgery and treated with prophylactic dose of 2 g ampicillin were enrolled to this prospective study. Blood samples were collected according to the study protocol and ampicillin plasma concentrations were measured using HPLC/UV system. A three-stage population pharmacokinetic model using nonlinear mixed-effects modelling approach was developed. Totally 273 blood samples obtained from 20 patients undergoing cardiac surgery with the use of the CPB and 20 patients without CPB use were analyzed. Two-comparmental model best fits ampicillin concentration-time data. Mean ± SD body weight-normalized ampicillin central and peripheral volume of distribution was 0.12 ± 0.02 L/kg and 0.15 ± 0.03 L/kg, respectively, while mean ± SD ampicillin clearance in typical patient with eGFR of 1.5 mL/s/1.73 m2 was 1.17 ± 0.05 L/h. The use of CPB did not significantly affect the pharmacokinetics of ampicillin. When administering 2 g of ampicillin before surgery, an additional dose should be administered to reach the PK/PD target of fT > MIC = 50% if the operation lasts longer than 430 min in patients with moderate to severe renal impairment, 320 min in patients with mild renal impairment, 220 min in patients with normal renal function status or 140 min in patients with an augmented renal clearance.

• MeSH
• ampicilin MeSH
• antibakteriální látky * terapeutické užití   MeSH
• dospělí MeSH
• kardiochirurgické výkony * MeSH
• kardiopulmonální bypass škodlivé účinky   metody   MeSH
• lidé MeSH
• prospektivní studie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Considering its very short elimination half-life, the approved oxacillin dosage might not be sufficient to maintain the pharmacokinetic/pharmacodynamics (PK/PD) target of time-dependent antibiotics. This study aimed to describe the population pharmacokinetics of oxacillin and to explore the probability of PK/PD target attainment by using various dosing regimens with oxacillin in staphylococcal infections. Both total and unbound oxacillin plasma concentrations retrieved as a part of routine therapeutic drug-monitoring practice were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were used to generate the theoretical distribution of unbound oxacillin plasma concentration-time profiles at various dosage regimens. Data from 24 patients treated with oxacillin for staphylococcal infection have been included into the analysis. The volume of distribution of oxacillin in the population was 11.2 L, while the elimination rate constant baseline of 0.73 h-1 increased by 0.3 h-1 with each 1 mL/s/1.73 m2 of the estimated glomerular filtration rate (eGFR). The median value of oxacillin binding to plasma proteins was 86%. The superiority of continuous infusion in achieving target PK/PD values was demonstrated and dosing according to eGFR was proposed. Daily oxacillin doses of 9.5 g, 11 g, or 12.5 g administered by continuous infusion have been shown to be optimal for achieving target PK/PD values in patients with moderate, mild, or normal renal function, respectively.

• Publikační typ
• časopisecké články MeSH

The objectives of this study were to develop a population pharmacokinetic model of prophylactically administered cefazolin in patients undergoing cardiac surgery with and without the use of the cardiopulmonary bypass of both existing types-standard (ECC) and minimallyu invasive extracorporeal circulation (MiECC)-and to propose cefazoline dosing optimization based on this model. A total of 65 adult patients undergoing cardiac surgery were recruited to this clinical trial. A prophylactic cefazolin dose of 2 g was intravenously administered before surgery. Blood samples were collected using a rich sampling design and cefazolin serum concentrations were measured using the HPLC/UV method. The pharmacokinetic population model was calculated using a nonlinear mixed-effects modeling approach, and the Monte Carlo simulation was used to evaluate the PK/PD target attainment. The population cefazolin central volume of distribution (Vd) of 4.91 L increased by 0.51 L with each 1 m2 of BSA, peripheral Vd of 22.07 L was reduced by 0.77 L or 0.79 L when using ECC or MiECC support, respectively, while clearance started at 0.045 L/h and increased by 0.49 L/h with each 1 mL/min/1.73 m2 of eGFR. ECC/MiECC was shown to be covariate of cefazolin Vd, but without relevance to clinical practice, while eGFR was most influential for the PK/PD target attainment. The standard dose of 2 g was sufficient for PK/PD target attainment throughout surgery in patients with normal renal status or with renal impairment. In patients with augmented renal clearance, an additive cefazolin dose should be administered 215, 245, 288 and 318 min after the first dose at MIC of 4, 3, 2 and 1.5 mg/L, respectively.

• Publikační typ
• časopisecké články MeSH

Background: Minimum mortality temperature (MMT) is an important indicator to assess the temperature-mortality association, indicating long-term adaptation to local climate. Limited evidence about the geographical variability of the MMT is available at a global scale. Methods: We collected data from 658 communities in 43 countries under different climates. We estimated temperature-mortality associations to derive the MMT for each community using Poisson regression with distributed lag nonlinear models. We investigated the variation in MMT by climatic zone using a mixed-effects meta-analysis and explored the association with climatic and socioeconomic indicators. Results: The geographical distribution of MMTs varied considerably by country between 14.2 and 31.1 °C decreasing by latitude. For climatic zones, the MMTs increased from alpine (13.0 °C) to continental (19.3 °C), temperate (21.7 °C), arid (24.5 °C), and tropical (26.5 °C). The MMT percentiles (MMTPs) corresponding to the MMTs decreased from temperate (79.5th) to continental (75.4th), arid (68.0th), tropical (58.5th), and alpine (41.4th). The MMTs indreased by 0.8 °C for a 1 °C rise in a community's annual mean temperature, and by 1 °C for a 1 °C rise in its SD. While the MMTP decreased by 0.3 centile points for a 1 °C rise in a community's annual mean temperature and by 1.3 for a 1 °C rise in its SD. Conclusions: The geographical distribution of the MMTs and MMTPs is driven mainly by the mean annual temperature, which seems to be a valuable indicator of overall adaptation across populations. Our results suggest that populations have adapted to the average temperature, although there is still more room for adaptation.

• Publikační typ
• časopisecké články MeSH

AIMS: While the effect of different types of incontinence on the quality of life (QoL) has been clearly documented, the information about the impact of incontinence severity on QoL in women is lacking. Therefore, we investigated whether increasingly severe degrees of incontinence were linearly correlated with poorer QoL. METHODS: We included 391 incontinent women and 81 continent volunteers in the study and assessed them in accordance with routine clinical practice. A 24 h pad-weight test was used to objectively quantify the incontinence severity. We then stratified participants according to incontinence type and severity and assessed correlations between incontinence severity and Patient Perception of Bladder Condition (PPBC), International Consultation on Incontinence short-form questionnaire (ICIQ-SF), and King's Health Questionnaire (KHQ) quality of life scores in the entire study population and in individual groups according to incontinence type. RESULTS: Minimal incontinence was associated with significant negative impact on QoL, as measured by all quality of life assement tools. There were nonlinear correlations between scores on individual questionnaires and daily leakage volumes. Stress urinary incontinence had a weaker impact on quality of life than urge or mixed incontinence, as measured by PPBC (P < 0.0001), KHQ part 1 (P < 0.0001), and KHQ part 2 (P < 0.001). Stress urinary incontinence also had a weaker impact on QoL than mixed incontinence as measured by ICI-Q (P = 0.007). CONCLUSIONS: This study demonstrated that even mild urinary leakage significantly reduces the QoL, while subsequent increase in the degree of incontinence has only minimal additional effect. There was no linear correlation between incontinence severity and QoL.

• MeSH
• dospělí MeSH
• inkontinence moči psychologie   MeSH
• kvalita života * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nelineární dynamika MeSH
• průzkumy a dotazníky MeSH
• senioři MeSH
• stresová inkontinence moči psychologie   MeSH
• urgentní inkontinence psychologie   MeSH
• vložky pro inkontinentní pacienty MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH