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During the last 10 years the European Medicines Agency (EMA) organized a number of workshops on modeling and simulation, working towards greater integration of modeling and simulation (M&S) in the development and regulatory assessment of medicines. In the 2011 EMA - European Federation of Pharmaceutical Industries and Associations (EFPIA) Workshop on Modelling and Simulation, European regulators agreed to the necessity to build expertise to be able to review M&S data provided by companies in their dossier. This led to the establishment of the EMA Modelling and Simulation Working Group (MSWG). Also, there was agreement reached on the need for harmonization on good M&S practices and for continuing dialog across all parties. The MSWG acknowledges the initiative of the EFPIA Model-Informed Drug Discovery and Development (MID3) group in promoting greater consistency in practice, application, and documentation of M&S and considers the paper is an important contribution towards achieving this objective.

Objective Elimination of sugammadex occurs predominantly via the kidneys, with the majority of the drug excreted unchanged in the urine. To date, most studies with sugammadex have been performed in non-Asian populations. The objectives of this open-label study were to determine the pharmacokinetics (PK) and safety of single-dose sugammadex (16 mg/kg) in healthy Chinese adult volunteers. Methods 12 Chinese subjects (6 male; 6 female) received intravenous sugammadex (16 mg/kg) as a 10-second bolus infusion. Blood samples were collected pre-sugammadex and at regular intervals up to 24 hours post-sugammadex for PK assessment. Safety was assessed via AEs, vital signs, electrocardiogram, and laboratory parameters. Results Following sugammadex 16 mg/kg infusion, peak sugammadex concentration was 197 μg/mL, clearance was 99.7 mL/min, and apparent volume of distribution at equilibrium was 10.5 L. Plasma sugammadex concentrations showed a polyexponential decline over time, with an overall geometric mean (CV%) terminal half-life of 145 minutes (17.9%) (139 minutes (17.7%) for males; 152 minutes (18.6%) for females). No influence of gender on the PK of sugammadex was observed. Three subjects experienced an adverse events (AE) (dysgeusia of mild intensity), which was considered possibly or probably related to sugammadex. There were no clinically significant changes in vital signs, electrocardiography or laboratory parameters. Conclusion PK of sugammadex (16 mg/kg) was characterized in healthy Chinese subjects. Overall between-subject variability on clearance and apparent volume of distribution was ~ 10%. Sugammadex was generally well tolerated.

Fondaparinux is a synthetic selective inhibitor of factor Xa recently approved for thromboprophylaxis after major orthopedic surgery. Determination of its concentration gives valuable insight into specific pharmacokinetics or safety studies. The aim of the study was to develop direct, sensitive, precise and accurate assays of fondaparinux sodium in different biological matrices. Consistency with the recommended chromogenic assay for low molecular weight heparin required a similar method. However, recent data indicated some variability in the determination of anti-Xa level between commercial chromogenic assays. Consequently, we developed and validated two chromogenic methods (A and B) for assaying fondaparinux in plasma and other biological matrices. The assays are calibrated with fondaparinux, a pure chemical entity, and the result is expressed as amount (microg) of the fondaparinux calibrator. Results showed that precision was lower than 5.2% in plasma or plasma water and 13% in placental medium. The accuracy was lower than 7.6% in plasma or plasma water and 10.2% in placental medium. The lower limit of quantification in plasma was 0.042 microg/mL with automated Method A and 0.019 microg/mL with Method B. The assay was not affected by the source of the samples, the presence of blood cells, EDTA, citrate or repeated cycles of freezing and thawing. The two chromogenic assays calibrated with fondaparinux sodium reach the equivalence criteria for plasma samples and provide reliable and reproducible results.