A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

Background: Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers. Methods: Male and non-pregnant female aged 18-50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study. Results: Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4-8 and 4-12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141-188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4-6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed. Conclusions: The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/201

Modelování volatility devizových kurzů

Import 22/07/2015The aim of this Diploma thesis is modelling and in-sample forecasting volatility of selected exchange rates using linear and nonlinear conditional heteroskedasticity models. The main aim of the thesis is supported by two partial aims. The first partial aim is to compare whether linear or nonlinear models are more efficient for modelling conditional heteroskedasticity for exchange rates. The second partial aim is to assess the suitability of estimated models to predict volatility. Tested data are time series of daily exchange rates modified to time series of daily logarithmic returns of Slovenian tolar, Cyprus pound, Slovakian koruna and Latvian lat against Euro. Observed period is divided into three parts in order to model volatility of all exchange rates in different relations of domestic countries to European Union. Thesis is divided into six parts including Introduction and Conclusion. Second and third chapter is theoretical and methodological, while the fourth and fifth chapter is practical and empirical.Cílem Diplomové práce je modelování volatility a ve výběru provedená predikce vybraných měnových kurzů za využití lineárních a nelineárních modelů podmíněné heteroskedasticity. Hlavní cíl práce je dále rozdělen na dva dílčí cíle. První z dílčích cílů se věnuje otázce, zda jsou k modelování měnových kurzů podmíněné heteroskedasticity vhodnější lineární nebo nelineární modely. Druhý dílčí cíl zohledňuje, zda jsou odhadnuté modely vhodné k predikování volatility. Testovaná data jsou časové řady denních měnových kurzů upravené na časové řady denních logaritmovaných výnosů Slovinského tolaru, Kyperské libry, Slovenské koruny a Lotyšského latu vůči Euru. Sledovaná časová perioda je rozdělena na tři části za účelem modelovat volatilitu všech měnových kurzů při různém vztahu domácí země vůči Evropské Unii. Práce je rozdělena na šest částí včetně úvodu a závěru. Druhá a třetí kapitola jsou teoretické a metodologické, zatímco čtvrtá a pátá kapitola jsou praktické a empirické.154 - Katedra financívýborn

Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants

Abstract SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor‐interacting serine/threonine protein kinase 1 (RIPK1). This phase I first‐in‐human healthy participant study (NCT05795907) was comprised of three parts: randomized, double‐blind, placebo‐controlled single ascending dose (SAD; part 1a); 14‐day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open‐label, single‐dose part 1b (PK‐cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well‐tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half‐lives (geometric mean) ranged between 5.7–8.0 h and 7.2–8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF‐to‐unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166‐RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547)

Bronchopulmonary Disposition of the Ketolide Telithromycin (HMR 3647)

Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens

MOESM1 of A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study

Additional file 1. McCarthy et al._Supplement. Supplementary data for probably related adverse events, detailed transaminase findings, individual parasite growth following inoculation (prior to ferroquine administration), pharmacokinetic model visualization, gametocytaemia and expanded methods for pharmacokinetic/pharmacodynamic modelling