Browsing by Subject "pharmacokinetics"
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(2016)This thesis work was carried out in Biology Section of Experimental Therapeutics Programme in Spanish National Cancer Research Center in Madrid. The aim of this work was to carry out characterization of ADME profile of novel protein kinase inhibitors synthesized by the Medicinal Chemistry Section of Experimental Therapeutics Programme. ADME refers to absorption, distribution, metabolism and excretion. ADME screening provides crucial information when choosing new chemical entities (NCEs) and lead compounds with desirable properties for further development and for clinical studies. ADME screening is carried out in the early discovery phase in order to avoid costly failures in the later stages. The protein kinase inhibitors used in this work were designed against three different targets. However, the targets cannot be disclosed in this work due to confidentiality reasons and thus they will be referred to as X, Y, and Z. The ADME characterization was performed in a high-throughput format to screen fast compounds with desired properties. To carry out ADME characterization for the novel compounds, several in vitro assays and in vivo pharmacokinetic studies were carried out. The work was started by setting up an LC-MS/MS detection method for each compound. All in all, LC-MS/MS detection method was set up for 63 new compounds. The detection method was used to analyze the results of different in vitro and in vivo studies. In vitro assays included kinetic solubility assay, parallel artificial membrane permeability assay (PAMPA), microsomal metabolic stability assay, plasma protein binding assay, and solubility in biological fluids. The solubility in biological fluids assay was performed only for the two compounds that were selected for the pharmacokinetic (PK) study. Pharmacokinetic properties of the compounds selected for the pharmacokinetic study using the Balb/C mice were further analyzed by their pharmacokinetic parameters. These parameters were calculated by applying non-compartmental model in the WinNonlin software. One compound, ETP-871, showed promising results in the pharmacokinetic study. Another compound ETP-827 was cleared too fast from the body. Too fast excretion is undesirable since low plasma concentration of the drug is insufficient to reach the therapeutic effect. For the compound ETP-827 a new PK study with higher dose was carried out. Due to the confidentiality reasons, these further studies are not presented in this work.
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(2017)Background: Dexmedetomdine is a α2-adrenergic receptor agonist, which by binding to the α2-adrenergic receptor in the sympathetic nervous system exhibits sedative effect. Additionally, it has an analgesic and anxiolytic effect. Dexmedetomidine is registered as a sedative for use in the intensive care unit and in USA, additionally, in surgical settings. The study was conducted to characterize the pharmacokinetics in healthy volunteers through pharmacokinetic analysis methods. Methods: The clinical study was conducted on healthy 10 voluntary subjects each receiving dose of 1 µg/kg both intravenously (IV) and subcutaneously (SC). The study session lasted for 10 hours, with a wash-out period of at least 7 days between consecutive administrations. Arterial blood samples were taken to determine the plasma concentrations of dexmedetomidine. The pharmacokinetics of the IV and SC dose were determined by noncompartmental analysis (NCA) and, additionally, population modeling using nonlinear mixed effects model (NONMEM) was used to determine the pharmacokinetics of the IV dose. Results: The population's mean clearance after the IV dose was 40.0 L/h and for SC 45.6 L/h. The elimination half-life was 2 hours for IV, whereas terminal half-life was 9 hours for the SC dose. The SC bioavailability was 120 %. From the population modeling the typical elimination clearance, volume of distribution in central compartment, inter-compartmental clearance, and volume of distribution in the second compartment were 39.6 L/h, 13.7 L, 116 L/h, and 77 L, respectively. Conclussion: The obtained pharmacokinetic parameter values from NCA for IV were in line with the results from previous studies. For the SC dose the pharmacokinetic parameter values had high SD indicating high inter-individual variations. However, when the 8th subject was excluded from data analysis less SD was obtained and the result resembled more the results from other extravascular studies. The pharmacokinetic population results for IV dexmedetomidine were similar to previous studies on healthy subjects. Weight was used as a covariate, and was modeled by allometrically scaling the parameters. From the results it is shown that the covariate improved the model's goodness of fit.
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(2019)Tutkimuksen tausta: Ibrutinibi on Brutonin tyrosiinikinaasin inhibiittori, jota käytetään kroonisen lymfaattisen leukemian (KLL), Waldenströmin makroglobulinemian, erilaisten lymfoomien ja kroonisen käänteishyljintäsairauden hoidossa. Se on tehokas etenkin KLL:n hoidossa, mutta sen käyttöä rajoittaa lääkityksen korkea hinta. Ibrutinibilla on pieni oraalinen biologinen hyötyosuus lähinnä merkittävän ensikierron metabolian vuoksi. Veritautia sairastavat potilaat ovat alttiita saamaan syviä sieni-infektioita niin itse taudin kuin sen hoitojenkin vuoksi. Sieni-infektioiden ehkäisy ja hoito ibrutinibia käyttävillä potilailla on kuitenkin ongelmallista, koska ibrutinibi on herkkä CYP3A4- välitteisille lääkeyhteisvaikutuksille ja suun kautta otettavat sienilääkkeet estävät kyseistä entsyymiä. Tutkimuksen tarkoitus oli selvittää sieni-infektioiden hoidossa käytetyn itrakonatsolin vaikutus ibrutinibin farmakokinetiikkaan ja voisiko lääkkeiden interaktiota käyttää hyväksi. Menetelmät: Kyseessä oli randomoitu, kaksivaiheinen, plasebokontrolloitu crossover-tutkimus. Tutkimukseen valittiin 11 tervettä ja tupakoimatonta vapaaehtoista miestä. Tutkittaville annettiin joko plaseboa tai 200 mg itrakonatsolia ensimmäisenä päivänä klo 8 ja 20 ja päivinä 2-4 klo 8. Kolmantena päivänä tutkittavat saivat joko 140 mg ibrutinibia plasebovaiheessa tai 15 mg ibrutinibia itrakonatsolivaiheessa noin tunti aamupalan jälkeen klo 9. Tutkittavista otettiin laskimoverinäytteitä säännöllisin väliajoin. Tulokset: Itrakonatsoli kymmenkertaisti altistumisen ibrutinibille verrattuna plaseboon. Lisäksi itrakonatsoli vähensi merkittävästi ibrutinibin pitoisuuksien vaihtelua yksilöiden välillä. Johtopäätökset: Ibrutinibin ja itrakonatsolin yhteiskäyttö voisi olla keino vähentää merkittävästi ibrutinibihoidon kustannuksia ja vaihtelua ibrutinibin pitoisuuksissa yksilöiden välillä. Lisäksi itrakonatsoli voisi tarjota samalla suojaa syviä sieni-infektioita vastaan.
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(2011)Ketoprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used for the treatment of pain in sheep and swine. Information of correct ketoprofen doses in different animal species is limited. The correct dose cannot be reliably extrapolated based on other species or human. The problem in cases of suspected overdose is knowing whether the given dose was toxic. The objective of the study with sheep was to figure out if the kinetics of ketoprofen is altered by a tenfold overdose, study the effect of the overdose to kidneys and find out a way to diagnose overdose by a simple urine test. The objective of the study with swine was to figure out the bioavailability and pharmacokinetics of ketoprofen after oral, intramuscular and intravenous administration. The most important variables were AUC0-_, Cmax and Tmax. Bioavailability was calculated based on intravascular administration. 30 mg/kg ketoprofen was administered intravenously to six sheep. The concentration of ketoprofen in sheep plasma was followed for 24 hours. Pharmacokinetic parameters were calculated afterwards. Blood and urine samples were analysed to detect enzyme markers indicating possible renal failure. The sheep were finished off 24 hours after the administration and the possible damage to kidneys was evaluated from histological samples. Ketoprofen was also administered to eight swine. The doses were 3 mg/kg of oral, intramuscular and intravascular, and 6 mg/kg of oral ketoprofen. The study was performed as a randomized, cross-over study. The concentration of ketoprofen in swine plasma was followed for 48 hours after administration. Pharmacokinetic parameters were calculated and bioequivalence evaluated afterwards. The in vivo -studies of both of the studies as well as the histological study of the kidneys, and the urine and blood analysis except for the analysis of ketoprofen concentration, were carried out by the researchers of the Faculty of Veterinary Medicine. Plasma ketoprofen concentrations were measured by high-performance liquid chromatography (HPLC). Drug concentration and pharmacokinetic analysis were carried out in the Faculty of Pharmacy. The tenfold dose of ketoprofen was toxic in sheep. Serum concentrations of urea and creatinine increased. Histological samples revealed acute tubular damage. Many urine enzyme concentrations increased. The rise of urine lactate dehydrogenase (LD) concentration was most significant and earliest. LD appears to be a potential marker of a toxic ketoprofen dose. Compared with the therapeutic dose, overdose did not affect ketoprofen elimination rate from plasma, so the kinetics of ketoprofen was not altered. AUC- and Cmax -values were over tenfold compared to the therapeutic dose, so the values did not rise linearly as the dose reached a toxic level. Bioequivalence of ketoprofen in swine was not observed between different routes of administration. The bioavailability was excellent in all routes of administration. Tmax was slightly over one hour after administration. Cmax and AUC were 5,1 mg/l and 32 mg l-1 h after oral 3 mg/kg dose and 7,6 mg/l and 37 mg l-1 h after intramuscular dose. The increases in AUC and Cmax were linear between the different dosages of oral ketoprofen. The difference of the elimination rates between oral and intravascular administration was statistically significant. Ketoprofen distribution volume and clearance did not differ significantly between different routes of administration.
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(2023)The opioid antagonist naloxone is a lifesaving medication used to treat opioid overdose. Non-invasive methods of administration for community use need to be developed further to fight the opioid crisis. An animal trial conducted in 2022 shows promising pharmacokinetic properties for ophthalmically administered naloxone. This review updates existing data on known non-invasive administration routes with a special focus on the novel idea of using the ophthalmic administration route. The literature search was limited to the Medline database and included human trials with pharmacokinetic data for select non-invasive administration routes of naloxone (ophthalmic, intranasal, buccal, and sublingual). Where pharmacokinetic data were unavailable, all human trials were included for that administration route. The intranasal administration route is by far the most studied of these. Pharmacokinetic trials show consistently good bioavailability and absorption with high-concentration intranasal formulations. For the ophthalmic route, only trials intending to achieve local effects were found although some unintentional systemic effects were observed. Data on the sublingual route are minimal, and no data for the buccal route were found. The ophthalmic administration route for naloxone has been dismissed in past research, shows pharmacokinetic viability and several other potential benefits, and should therefore be further investigated in humans. The FDA-approved intranasal products are the gold standard, and future research should be benchmarked against them.
Now showing items 1-6 of 6