Pharmacokinetics, pharmacodynamics, and safety of fesomersen, a novel antisense inhibitor of factor XI, in healthy Chinese, Japanese, and Caucasian volunteers.

The inhibition of coagulation factor XI (FXI) presents an attractive approach for anticoagulation as it is not expected to increase the risk of clinically relevant bleeding and is anticipated to be at least as effective as currently available anticoagulants. Fesomersen is a conjugated antisense oligonucleotide that selectively inhibits the expression of FXI. The article describes three clinical studies that investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of fesomersen after subcutaneous (s.c.) injection to healthy participants. The studies included participants from diverse ethnic backgrounds (Caucasian, Japanese, and Chinese). Fesomersen demonstrated good safety and tolerability in all three studies. No major bleeding events were observed. After single-dose s.c. injection, fesomersen was rapidly absorbed into the systemic circulation, with maximum fesomersen-equivalent (fesomersen-eq) concentrations (Cmax) in plasma observed within a few hours. After reaching Cmax, plasma fesomersen-eq concentrations declined in a biphasic fashion. The PD analyses showed that the injection of fesomersen led to dose-dependent reductions in FXI activity and increases in activated partial thromboplastin time (aPTT). The maximum observed PD effects were reached between Day 15 and 30, and FXI activity and aPTT returned to near-baseline levels by Day 90 after a single dose. The PK/PD profiles after a single injection were similar among the various ethnic groups. Collectively, the study results suggest that fesomersen has a favorable safety profile and predictable and similar PK and PD profiles across Chinese, Japanese, and Caucasian participants.

Role of computed tomography texture analysis using dual-energy-based bone marrow imaging for multiple myeloma characterization: comparison with histology and established serologic parameters.

OBJECTIVE: To identify textural features on dual-energy CT (DECT)-based bone marrow images in myeloma which correlate with serum markers of myeloma activity and the degree of medullary involvement. METHODS: A total of 110 patients (63.0 ± 11.0 years, 51 female) who underwent unenhanced whole-body DECT between September 2015 and February 2019 were retrospectively included, which was approved by our institutional ethics committee with a waiver of the informed consent requirement. All patients had current hematologic laboratory tests. Using DECT post-processing, non-calcium bone marrow images were reconstructed. The vertebral bodies T10-L5 were segmented for quantification of textural features, which were compared with serologic parameters and myeloma stages by the Mann-Whitney U test. In a subgroup of 56/110 patients with current bone marrow biopsies, textural features were correlated with the degree of bone marrow infiltration. RESULTS: First-order features were higher in patients with advanced stage of myeloma (p < .02), whereas the 2nd-order "gray-level co-occurrence matrix (GLCM) cluster prominence" was lower (p < .04). In patients with elevated serum-free light chains (SFLC) or kappa/lambda SFLC ratio above 1.56, the "entropy" and 2nd-order GLCM features were lower (p < .03). The degree of bone marrow infiltration correlated with 1st-order features (e.g., "uniformity"; rP = 0.49; p < .0001), whereas "entropy" and 2nd-order GLCM features were negatively correlated (e.g., "difference entropy"; rP = - 0.54; p < .0001). CONCLUSIONS: CT textural features applied on non-calcium bone marrow images correlate well with myeloma-related serologic parameters and histology showing a more uniform tissue structure and higher attenuation with increasing medullary infiltration and could therefore be used as additional imaging biomarkers for non-invasive assessment of medullary involvement. KEY POINTS: • Texture analysis applied on dual-energy reconstructed non-calcium bone marrow images provides information about marrow structure and attenuation. • Myeloma-related serologic parameters and the degree of myeloma cell infiltration correlate with 1st- and 2nd-order features which could be useful as additional imaging biomarkers for non-invasive assessment of medullary involvement.

Mid-term response assessment in multiple myeloma using a texture analysis approach on dual energy-CT-derived bone marrow images - A proof of principle study.

PURPOSE: To identify textural features on dual-energy CT (DECT)-generated virtual non calcium (VNC) bone marrow images in a small group of patients with multiple myeloma undergoing systemic treatment which could potentially help for mid-term response assessment. METHODS: 44 patients (59.1 ±â€¯11.2 yr.) with multiple myeloma who underwent unenhanced whole-body reduced-dose DECT before and after systemic therapy were evaluated. All patients had current hematologic laboratory tests including serum levels of immunoglobulins, albumin, and total proteins. Using DECT post-processing, bone marrow images of the axial skeleton were reconstructed. The vertebral bodies T10-L5 were segmented for quantification of 1st order (n = 18) and 2nd order Gray Level Co-occurrence Matrix (GLCM) textural features (n = 23) based on an open-source radiomics library (Pyradiomics), which were then compared with the hematologic response category to treatment. Five patients underwent only active surveillance at intervals after previous successful therapy. RESULTS: According to hematologic diagnosis, 29 patients were classified as complete response (CR), 10 as partial response (PR) and 5 as stable disease (SD). We observed a significant drop of the 1st order textural features "10th percentile" (p = 0.009), "median" (p = 0.01), and "minimum" (p < 0.0001) after treatment, whereas the 1st order feature "range" (p = 0.0004) and the 2nd order GLCM feature "difference variance" (p = 0.007) significantly increased in patients experiencing CR. A similar trend, however, without statistical significance, could be observed in patients achieving PR after treatment. 2nd order GLCM feature "difference variance" proved to be a significant discriminator (p = 0.01) between patients with CR and PR (sensitivity 0.93, specificity 0.70) for a cut-off value of -0.28. In patients classified CR, both the mean serum protein and the beta-2 microglobulin decreased after treatment, whereas the serum albumin increased (p < 0.01). The same trend without significance could be observed in patients classified PR. CONCLUSIONS: Changes in textural features applied on VNC bone marrow images in the pre- and posttreatment settings correlate well with myeloma-specific hematologic parameters and provide complementary information for the assessment of the late effects of treatment on the bone marrow.

Evaluation of pharmaceutical concerns in Germany: frequency and potential reasons.

BACKGROUND: Generic substitution can have unintended consequences. In Germany, brand name to generic or generic to generic switching is mainly driven by rebate contracts. Frequent switching may raise concerns about bio- and therapeutic equivalence. Expected patient confusion may result in compromised medication adherence or new onset of other drug-related problems. Since 2008, pharmacists are allowed to deviate from rebate contracts by denying substitution due to pharmaceutical concerns on an individual basis. OBJECTIVES: To explore the frequency of documented pharmaceutical concerns in Germany between July 2011 and December 2013 and to identify the medicines most frequently related to pharmaceutical concerns in 2013. METHODS: We analyzed documented pharmaceutical concerns in all prescribed drugs at the expense of any statutory health insurance company requiring pharmacies' generic substitution according to rebate contracts. RESULTS: Since July 2011, the frequency of documented pharmaceutical concerns in relation to prescribed drug products with rebate contracts requiring substitution increased consistently and doubled between July 2011 and July 2013. Overall in 2013, the trend of the two previous years continued and reached approximately 1.5%. The most affected drugs/drug classes were thyroid hormones (in particular combinations with iodide; 15.9%) followed by ondansetron (12.5%), and levothyroxine (11.3%). For all drugs/drug classes under investigation, product-, patient- or disease-related aspects could be identified which are potential reasons to deny substitution and to document pharmaceutical concerns. CONCLUSIONS: Although there is no electronic recording of the specific reasons for pharmaceutical concerns in claims data, our analyses support the assumption that pharmacists make use of this instrument based on individual clinical decisions and as required by contract. Pharmaceutical concerns are, therefore, an important instrument for pharmacies to refuse generic substitution. They are considered to prevent compromised medication safety and to assure pharmacotherapy effectiveness in a generic substitution environment driven by low drug prizes above all.

Evaluation of pharmaceutical concerns in Germany: frequency and potential reasons

Background: Generic substitution can have unintended consequences. In Germany, brand name to generic or generic to generic switching is mainly driven by rebate contracts. Frequent switching may raise concerns about bio- and therapeutic equivalence. Expected patient confusion may result in compromised medication adherence or new onset of other drug-related problems. Since 2008, pharmacists are allowed to deviate from rebate contracts by denying substitution due to pharmaceutical concerns on an individual basis. Objectives: To explore the frequency of documented pharmaceutical concerns in Germany between July 2011 and December 2013 and to identify the medicines most frequently related to pharmaceutical concerns in 2013. Methods: We analyzed documented pharmaceutical concerns in all prescribed drugs at the expense of any statutory health insurance company requiring pharmacies’ generic substitution according to rebate contracts. Results: Since July 2011, the frequency of documented pharmaceutical concerns in relation to prescribed drug products with rebate contracts requiring substitution increased consistently and doubled between July 2011 and July 2013. Overall in 2013, the trend of the two previous years continued and reached approximately 1.5%. The most affected drugs/drug classes were thyroid hormones (in particular combinations with iodide; 15.9%) followed by ondansetron (12.5%), and levothyroxine (11.3%). For all drugs/drug classes under investigation, product-, patient- or disease-related aspects could be identified which are potential reasons to deny substitution and to document pharmaceutical concerns. Conclusions: Although there is no electronic recording of the specific reasons for pharmaceutical concerns in claims data, our analyses support the assumption that pharmacists make use of this instrument based on individual clinical decisions and as required by contract. Pharmaceutical concerns are, therefore, an important instrument for pharmacies to refuse generic substitution. They are considered to prevent compromised medication safety and to assure pharmacotherapy effectiveness in a generic substitution environment driven by low drug prizes above all (AU)

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