Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both Cmax and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC0-inf after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC0-inf of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
- MeSH
- aplikace orální MeSH
- biologická dostupnost MeSH
- dasatinib MeSH
- klinické křížové studie MeSH
- lidé MeSH
- omeprazol * farmakokinetika MeSH
- plocha pod křivkou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
One of the major concerns for all in vivo experiments is intra- and inter-subject variability, which can be a great source of inaccuracy. The aim of this study is, therefore, to estimate the ability of parallel vs. cross-over design studies in order to describe the relative pharmacokinetic performance of the studied drug formulations. We analyzed the data from a drug development program that examined the performance of innovative abiraterone acetate formulations against the identical reference product in three stages. In stages 1-3, groups A-F were dosed with the reference product once in a parallel manner. Stage 4 was performed to evaluate the intra-individual variability (IIV) by repeated administration of the reference product to the same animals. Although the geometric mean (90% CI) values of abiraterone AUClast in groups A-F were similar to the IIV group (24.36 (23.79-41.00) vs. 26.29 (20.56-47.00) mg/mL·min·g), the results generated in the isolated parallel groups provided imprecise estimates of the true AUClast values ranging from 9.62 to 44.62 mg/mL·min·g due to chance. Notably, in 4 out of 15 possible pair comparisons between the parallel groups, the confidence intervals did not include 100%, which is the true ratio for all comparisons tested after identical formulation administration to all groups. A cross-over design can significantly improve the methodology in short-term comparative pre-clinical pharmacokinetic studies, and can provide more precise and accurate results in comparison to more traditional pre-clinical study designs.
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- Azurion,
- MeSH
- intervenční radiologie metody přístrojové vybavení MeSH
- nemoci cév diagnóza terapie MeSH
- radiologické oddělení nemocnice organizace a řízení MeSH
- radiologie * MeSH
- rentgendiagnostika MeSH
- Publikační typ
- novinové články MeSH
- rozhovory MeSH
The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II).
- MeSH
- antiflogistika nesteroidní * aplikace a dávkování chemie farmakokinetika MeSH
- chemie farmaceutická MeSH
- citráty chemie MeSH
- fixní kombinace léků MeSH
- klinické křížové studie MeSH
- koncentrace vodíkových iontů MeSH
- lidé MeSH
- meloxikam MeSH
- omeprazol * aplikace a dávkování chemie farmakokinetika MeSH
- pomocné látky chemie MeSH
- prášky, zásypy, pudry MeSH
- protivředové látky * aplikace a dávkování chemie farmakokinetika MeSH
- terapeutická ekvivalence MeSH
- thiaziny * aplikace a dávkování chemie farmakokinetika MeSH
- thiazoly * aplikace a dávkování chemie farmakokinetika MeSH
- tobolky MeSH
- uvolňování léčiv MeSH
- želatina chemie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
V předložené práci je popsána metodika a prvé zkušenosti s vyšetřováním žilního systému DK pomoci MDCT v souboru 32 pacientů. MDCT flebografie je rozdělena na přímou a nepřímou metodu podle způsobu aplikace kontrastní látky. Dále je popsáno začlenění této metody do vyšetřovacího algoritmu žilního systému dolních končetin.
The article presents the methods and first experience with lower limb vein system examination by the multidetector CT in our group containing 32 patients. The MDCT phlebography can be direct or indirect, depending on the mode of contrast medium administration. The place of this method in lower limb vein system examination algorithm is also described.
- Klíčová slova
- Quinlukast,
- MeSH
- antiastmatika farmakologie chemie krev MeSH
- finanční podpora výzkumu jako téma MeSH
- krevní buňky účinky léků MeSH
- krevní proteiny chemie MeSH
- lidé MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
