Q88392068
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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
AIM: The aim of this study was to evaluate adherence to spironolactone in a group of unselected patients with arterial hypertension by analysis of measured serum spironolactone and canrenone concentrations according to a proposed two-step decision scheme based on pharmacokinetic considerations. MATERIALS AND METHODS: Simulation of serum concentration-time profiles of spironolactone and canrenone based on population pharmacokinetic parameters described in literature and a body weight-normalized spironolactone dose / canrenone level nomogram derived from a group of adherent patients with conservatively treated primary hyperaldosteronism, were used to create a two-step decision scheme. 71 outpatients treated with spironolactone for resistant hypertension with spironolactone and canrenone serum concentrations measured between 2018 and 2021 were analyzed according to the proposed scheme. We compared our proposed methodology to the standard approach for adherence testing. RESULTS: With the most sensitive traditional approach to adherence assessment through detectable serum concentrations of spironolactone and/or canrenone, 9 (12.7%) non-adherent patients were identified. With our two-step assessment of adherence, we were able to identify 18 (25.4%) non-adherent patients. CONCLUSION: Consideration of the pharmacokinetic properties of parental drug and its metabolite led to improved sensitivity in non-adherence detection in patients with arterial hypertension. This approach enables better interpretation of measured spironolactone and canrenone serum concentrations and should be used in clinical practice.
- MeSH
- adherence k farmakoterapii * MeSH
- antagonisté mineralokortikoidních receptorů farmakokinetika MeSH
- dospělí MeSH
- hyperaldosteronismus farmakoterapie krev MeSH
- hypertenze * farmakoterapie MeSH
- kanrenon * farmakokinetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- pilotní projekty MeSH
- senioři MeSH
- spironolakton * farmakokinetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Continuous caudal epidural analgesia used intraoperatively in children is an effective and safe technique. However, in preterm neonates, developmental factors may significantly affect levobupivacaine disposition, leading to variable pharmacokinetics, pharmacodynamics, and potential large-variable systemic toxicity of local anesthetics. OBJECTIVE: To our knowledge, this is the first case report describing the disposition of levobupivacaine used for intraoperative caudal epidural analgesia in a preterm neonate treated for the postoperative pain profile. METHOD: 4-days old neonate (postmenstrual age 35+5, weight 2140 g) with congenital anal atresia received continuous caudal epidural long-term analgesia (loading dose 1.694 mg/kg, initial infusion 0.34 mg/kg/hour) before correction surgery. The blood samples were obtained at 1.0, 1.5, 6.5, 12, and 36.5 h after the start of epidural infusion. The pharmacokinetic profile of levobupivacaine was determined by using the Stochastic Approximation Expectation Maximization algorithm. COMFORT and NIPS pain scores were used for the assessment of epidural analgesia. RESULTS: The levobupivacaine absorption rate constant, apparent volume of distribution, apparent clearance, and elimination half-life were 10.8 h-1, 0.9 L, 0.086 L/h, and 7.3 h, respectively. CONCLUSION: The results confirm our hypothesis of altered pharmacokinetics in the preterm neonate. Therefore, levobupivacaine therapy in these patients should be carefully monitored. Since therapeutic drug monitoring of levobupivacaine is not established in clinical routines, we suggest monitoring the intraoperative pain profile using validated scores. TRIAL REGISTRATION: EudraCT number: 2020-000595-37.
- MeSH
- anestetika lokální MeSH
- bupivakain * MeSH
- dítě MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- epidurální analgezie * škodlivé účinky metody MeSH
- levobupivakain terapeutické užití MeSH
- lidé MeSH
- novorozenec MeSH
- pooperační bolest farmakoterapie etiologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- kazuistiky MeSH
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease with unknown cause. It mainly affects joints and, without proper treatment, negatively impacts their movement, causes painful deformities, and reduces the patients' quality of life. Current treatment options consist of various types of disease-modifying antirheumatic drugs (DMARDs), however 20-30% of patients are partially resistant to them. Therefore, development of new drugs is necessary. Possible option are compounds exhibiting their action via endocannabinoid system, which plays an important role in pain and inflammation modulation. One such compound - cannabidiol (CBD) has already been shown to attenuate synovitis in animal model of RA in in vivo studies. However, it has low bioavailability due to its low water solubility and lipophilicity. This issue can be addressed by preparation of a lipid containing formulation targeting lymphatic system, another route of absorption in the body. Materials and Methods: CBD-containing emulsion was prepared by high-shear homogenization and its droplet size distribution was analysed by optical microscopy. The relative oral bioavailability compared to oil solution as well as total availability of CBD were assessed in a cross-over study in rats and absorption of CBD via lymphatic system was observed. The effect of CBD on the animal model of RA was determined. Results: Compared to oil solution, the emulsion exhibited higher absolute oral bioavailability. Significant lymphatic transport of CBD was observed in all formulations and the concentrations in lymph were calculated. The therapeutic effect of CBD on RA was confirmed as an improvement in clinical symptoms as well as morphological signs of disease activity were observed during the study. Conclusion: In this work, we prepared a simple stable emulsion formulation, determined the pharmacokinetic parameters of CBD and calculated its absolute bioavailability in rats. Moreover, we successfully tested the pharmaceutical application of such a formulation and demonstrated the positive effect of CBD in an animal model of RA.
- MeSH
- aplikace orální MeSH
- bolest farmakoterapie MeSH
- emulze MeSH
- kanabidiol * farmakologie chemie MeSH
- klinické křížové studie MeSH
- krysa rodu rattus MeSH
- kvalita života MeSH
- revmatoidní artritida * farmakoterapie MeSH
- voda MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Mycophenolate mofetil (MMF) is an immunosuppressant drug approved for prophylaxis of transplant rejection in patients undergoing solid organ transplantation and is further employed in management of various autoimmune disorders. MMF exhibits notable pharmacokinetic inter- and intraindividual variability necessitating tailored therapeutic approaches to achieve optimal therapeutic outcomes while mitigating risks of adverse effects. The objective of this review was to summarize factors that influence the pharmacokinetics of MMF and its active metabolite mycophenolic acid in order to deduce recommendations for personalized treatment strategies. Presumed predictors were analysed in relation to each of the four pharmacokinetic phases, providing tools and targets for MMF dosing optimization amenable to clinical implementation.
- MeSH
- imunosupresiva * farmakokinetika aplikace a dávkování MeSH
- individualizovaná medicína MeSH
- kyselina mykofenolová * farmakokinetika aplikace a dávkování MeSH
- lidé MeSH
- rejekce štěpu prevence a kontrola MeSH
- transplantace orgánů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The bioavailability of rivaroxaban at the higher doses (15 and 20 mg) is considerably reduced when the drug is administered on an empty stomach. This can lead to inadequate anticoagulant effect, and therefore, it is recommended to use the higher doses at fed state. However, proper posology may represent a barrier for some patients. Therefore, the aim of this study was to evaluate innovative rivaroxaban-containing formulations designed to eliminate the food effect to ensure reliable absorption and thus to improve patient adherence with the treatment. Three prototypes (Cocrystal, HPMCP and Kollidon) with rivaroxaban were developed and their bioavailability and food effect in comparison to the reference product was tested in open label, randomized, single oral dose, crossover studies, where test products were administered under fasting and fed conditions and the reference product was administered under fed conditions. Comparable bioavailability for all tested prototypes both under fed and fasting conditions was demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the concentration-time curve remained within the standard acceptance range of 80.00%-125.00%. An innovative immediate release form of rivaroxaban with no food effect on drug bioavailability has been developed, which may represent an important step toward increasing adherence, improving treatment outcome and reducing health care costs.
- MeSH
- aplikace orální MeSH
- biologická dostupnost * MeSH
- dospělí MeSH
- inhibitory faktoru Xa farmakokinetika aplikace a dávkování MeSH
- interakce mezi potravou a léky * MeSH
- jídla MeSH
- klinické křížové studie * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- omezení příjmu potravy * MeSH
- příprava léků metody MeSH
- rivaroxaban * farmakokinetika aplikace a dávkování MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie 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
Daprodustat, also known under the trade name DUVROQ, is a small molecule developed by GlaxoSmithKline, which has become a promising drug in the field of anemia treatment in patients with chronic kidney disease. Daprodustat belongs to a group of drugs called hypoxia-inducible factor prolyl hydroxylase inhibitors. These drugs interfere with the regulation of erythropoietin, which is a key factor in the production of red blood cells. This drug was approved in Japan in June 2020 and clinical studies with it are ongoing in several countries around the world, where they focus on evaluating the effectiveness and safety in various populations of patients with chronic kidney disease.
Second-generation antipsychotics (SGAs), also known as atypical antipsychotics, are a newer class of antipsychotic drugs used to treat schizophrenia, bipolar disorder, and related psychiatric conditions. The plasma concentration of antipsychotic drugs is a valid measure of the drug at its primary target structure in the brain, and therefore determines the efficacy and safety of these drugs. However, despite the well-known high variability in pharmacokinetics of these substances, psychiatric medication is usually administered in uniform dosage schedules. Therapeutic drug monitoring (TDM), as the specific method that can help personalised medicine in dose adjustment according to the characteristics of the individual patient, minimizing the risk of toxicity, monitoring adherence, and increasing cost-effectiveness in the treatment, thus seems to be an elegant tool to solve this problem. Non-response to therapeutic doses, uncertain adherence to medication, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM of SGAs. This review aims to summarize an overview of the current knowledge and evidence of the possibilities to tailor the dosage of selected SGAs using TDM, including the necessary pharmacokinetic parameters for personalised pharmacotherapy.
- MeSH
- antipsychotika * farmakokinetika terapeutické užití MeSH
- lidé MeSH
- monitorování léčiv * metody MeSH
- schizofrenie farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
