Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers.

The opportunistic fungal infection cryptococcal meningoencephalitis is a major cause of death among people living with HIV in sub-Saharan Africa. We report pharmacokinetic (PK) and safety data from a randomized, four-period crossover phase I trial of three sustained-release (SR) oral pellet formulations of 5-flucytosine conducted in South Africa. These formulations were developed to require less frequent administration, to provide a convenient alternative to the current immediate release (IR) formulation, A. Formulations B, C, and D were designed to release 5-flucytosine as a percentage of the nominal dose in vitro. We assessed their safety and PK profiles in a single dose (1 × 3000 mg at 0 h), relative to commercial IR tablets (Ancotil 500 mg tablets; 3 × 500 mg at 0 h and 3 × 500 mg at 6 h) in healthy, fasted participants. Forty-two healthy participants were included. All treatments were well-tolerated. The primary PK parameters, maximum observed plasma concentration (Cmax ) and area under the concentration-time profiles, were significantly lower for the SR formulations than for the IR tablets, and the geometric mean ratios fell outside the conventional bioequivalence limits. The median maximum time to Cmax was delayed for the SR pellets. Physiologically-based PK modeling indicated a twice-daily 6400 mg dose of SR formulation D in fasted condition would be optimal for further clinical development. This regimen is predicted to result in a rapid steady-state plasma exposure with effective and safe trough plasma concentration and Cmax values, within the therapeutic boundaries relative to plasma exposure after four times per day administration of IR tablets (PACTR202201760181404).

European Federation for Exploratory Medicines Development Lyon Conference 2019: The Changing Landscape of Early Medicines Development-Be Prepared.

The second biennial conference of the European Federation for Exploratory Medicines Development (EUFEMED) was the result of a continued effort of EUFEMED to gather all stakeholders of exploratory clinical drug development to evaluate and discuss recent developments in the field. The conference focused on how the landscape around early clinical development is changing and how clinical pharmacologists might prepare for these changes. A preconference workshop gave consideration to the impact that modeling and simulation, including physiology-based pharmacokinetic strategies, is having on the practice of clinical development. A second workshop looked at the challenges introduced by biological agents. The keynote address explored the potential role of virtual trials in early medicines development with emphasis on how models can help to understand and inform the drug development process. Presentations that followed covered a broad range of subjects including the potential impact of digital support on study performance in early phase development, extending from recruitment to remote data collection, lay person summaries, data transparency, and ethical considerations for trials in healthy subjects. The second day of the conference focused on future regulatory challenges in the field of early clinical development (including Brexit) and how to prepare for changes in the landscape. Subjects covered included new approaches and designs in oncology, the introduction of more complex study designs and digital biomarkers. Presentations given by invited speakers are published at https://www.eufemed.eu/download-presentations-of-the-lyon-conference-2019/.

EUFEMED London Conference 2017: Exploratory Medicines Development: Innovation and Risk Management.

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/.

Characterizing "Adversity" of Pathology Findings in Nonclinical Toxicity Studies: Results from the 4th ESTP International Expert Workshop.

The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.

A safety grading scale to support dose escalation and define stopping rules for healthy subject first-entry-into-man studies: some points to consider from the French Club Phase I working group.

AIM: To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first-entry-into-man (FIM) studies conducted in young healthy subjects. METHODS: A three-level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A 'combined method' based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. RESULTS: Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. CONCLUSIONS: This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some 'points to consider' helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities.

Pharmacokinetic and pharmacodynamic interactions between metoprolol and dronedarone in extensive and poor CYP2D6 metabolizers healthy subjects.

As dronedarone a new noniodinated antiarrhythmic agent structurally related to amiodarone could inhibit CYP2D6 and is planned to be associated with beta-blockers, interactions with CYP2D6 metabolized beta-blockers such as metoprolol, have to be studied. Forty-nine healthy male subjects genotyped for CYP2D6 were included in a randomized, double-blind, placebo-controlled study. Metoprolol was administrated during 13 days (200 mg/day). After the initial 5 days, subjects received placebo (n = 12), 800 mg (n = 6), 1200 mg (n = 9), or 1600 mg (n = 17) of dronedarone daily during eight additional days. Pharmacokinetic parameters of metoprolol were investigated at day 5 and at day 13 in 44 subjects, 39 extensive metabolizers and five poor metabolizers for CYP2D6. Cardiac contractility function was evaluated by the rate-corrected electromechanical systole duration (QS2i) and the mean velocity of endocardial circumferential fiber shortening (Vcfmean). Cmax and AUC0--24 h of metoprolol increased from days 5 to 13 in proportion to dronedarone dose only in CYP2D6 extensive metabolizers genotyped subjects (P < 0.001). In all subjects, from days 5 to 13, Vcfmean decreased and QS2i significantly increased in dronedarone groups. The Vcfmean changes were however significant only with the 1600 mg dronedarone dose compared with placebo while QS2i changes induced by addition of dronedarone were significant compared with placebo at all dose levels. Between days 5 and 13, QS2i and Vcfmean changes were significantly correlated with both dronedarone concentrations at day 13 and with metoprolol concentration changes between days 5 and 13. Plasma metoprolol concentrations were highest in poor metabolizer subjects and dronedarone did not further increase their level but increased QS2i in the two subjects receiving the 1600 mg dose. Addition of dronedarone (800-1600 mg daily) to metoprolol (200 mg daily) increases bioavailability of metoprolol in CYP2D6 extensive metabolizers and induces an additive dronedarone dose-dependent negative inotropic effect. Nevertheless at 800 mg daily (anticipated therapeutic dose) these effects were modest.

The pharmacodynamics of tinzaparin in healthy volunteers.

We report the pharmacodynamic properties of tinzaparin (175 U/kg antifactor Xa) given as a single daily administration for 5 consecutive days to 14 healthy volunteers as a known safe, effective treatment of deep vein thrombosis and pulmonary embolism. The Cmax for antifactor Xa (0.87 +/- 0.15 U/ml) was associated with a 2.4 +/- 0.5-fold prolongation of the activated partial thromboplastin time (APTT) and a high antithrombin activity (0.38 +/- 0.1 U/ml). The Cmax value of antifactor Xa was 1.5- and twofold lower than those generated by similar doses of nadroparin and enoxaparin respectively. The clearance of antifactor Xa activity (1.29 +/- 0.2 l/h) was 1.5- and twofold greater than those reported for nadroparin and enoxaparin respectively. These results indicated that the antithrombotic and prohaemorrhagic effects of a low molecular weight heparin were independent from the absolute levels of antifactor Xa activities and from the prolongation of the APTT.