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CSL730 TDM/Hemapen (CSL730 (Administered by subcutaneous…

- - - - Flow
        
        Whole blood: Fc gamma receptors in circ. leukocyte subsets
      - Soluble biomarkers
        
        Whole blood: inhibition of FcyR activation & exploratory biomarkers
        
        p/tSYK
        
        Safety markers: IgG, cytokines, inflammatory markers, complement...
        
        IL-1Ra
        
        IL-6
      - PGx
        
        Whole blood: genetic profile
- - - - Sample Collection
        
        Is there any interference from the collection material itself (blank?)
        
        Is drying a concern? Improper dryign may affect analyte stability/contamination
        
        Incorporation of an internal standard
        
        Elution efficiency
      - Matrix used for Cal. curves and internal QCs
        
        Whole blood? Does HemaPen have an anticoagulant? Impractical to prepare spiked samples in anti-coagulated blood
        
        If not, can we draw pre-dose aliquots from the patient for noanticoagulent/anticoagulent testing?
        
        prep of spiked Cal. and QCs may require HT or erythrocyte volume fraction adjustment
        
        Most commercial assays have not been validated for use with DBS and therefore additional regulatory approval may be required
    - - Potassium measurement
      - Spectroscopy
        
        noncontact diffuse reflectance
        
        near-infrared
      - Sulfolyser reagetnt
    - - TDM helps maintain drug at trough concnetrations and can prevent deleterious anti-drug antibody formation
      - Faster turnaround time
      - Simplified specimen transport and logistics
  - - - MD- Stress Testing
        
        Assess time sensitivity
        
        Analyze 50-60C for atleast 2 days to mimic aged samples?
        
        Other factors: humidity and exposure to light
        
        Volume & hematocrit & homogeneity
        
        Stability concerns for enzymatic and oxidation sensitive analytes
      - For therapeutic drug monitoring: cal. range conc. range should be representative of expected patent sample conc
        
        correlation between DBS and venous blood appears to be analyte specific
      - Suggested 412 DBS required for Validation (258 DBS if volume, HT, volcano, carryover and stability @ 60C are not assessed). Further decreases if carryover and nr. of Stability&Recovery replicates are reduced
        
        Selectivity (n= 12) 6BLK+6LLOQ
        
        Calibration curve (30) 6 Cal levels x 5 days
        
        Accuracy & precision (n=24) 4 QC levels (duplicate)x 3days
        
        Dilution Integrity (n=6) 1 QC level (duplicate) :x 3 days
        
        Extraction solvent spiked with QC level of standard
        
        Carryover (n=10) Blank & Zero sample x 5 days
        
        test for sampling contam (more an issue for PCR-based techniques)
        
        Recovery/Mat effect/process efficiency (n=170)
        
        2 QC levels x 6 donors (5 replicates)
        
        1 donor x 3 HT levels x 2 QC levels
        
        Matuszewski approach?
        
        2 QC levels for Standard solutions (5 replicates)
        
        Stability (n=40)
        
        2 QCs @ 1 HT level (5 replicates)
        
        4 Timepoints @ RT & 60C
        
        Volume/HT/Volcano Effect (n=120)
        
        2 QC levels @ 3 HT levels (5 replicates)
        
        4 volumes (3x vol. levels for central punch and 1x high peripheral punch vol)
      - Clinical Validation: Comparing DBS to Venous blood/plasma/serum
        
        Recommended min. 40 samples from 25 subjects (for blood and DBS)
        
        Differences in peripheral vs venous blood (distribution phase)
        
        HT determination
        
        not necessary for HT-dependent method if HT range in that specific population is narrow & within method acceptance limits
        
        HT effect less pronounced with fixed spot volume
        
        Comparing DBS to venous blood/anticoagulated blood//serum/plasma
        
        drug may bind to plasma components, accumulate in RBCs which may impact results between matrices
        
        Analytical methods can be used to include HT correction
      - Stats Interpretation
        
        Regression analysis
        
        weighted Deming regression
        
        Passing-Bablok
        
        Assess agreement/estimate bias
        
        Bland-Altman
        
        Decide beforehand what a clinically relevant or acceptable bias is beforehand (limits of agreement)
  - - - Val. of biomarkers from DBS vsSerum. Buxton et al. 2016 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812568/
        
        Established serum to DBS equivalence rather than comparing to whole blood
        
        DBS hs greater variability compared to venous blood and therefore less reliable on an individual level
    - - https://www.researchgate.net/publication/332095120_Dried_blood_samples_can_support_monitoring_of_infliximab_concentrations_in_patients_with_inflammatory_bowel_disease_A_clinical_validation
        
        Elution buffer: PBS-T/0.05%NaN3 vigorously shaking overnight (>17h) on orbital shaker. Eluate kept at 4C
        
        HT conversion of DBS
        
        Fixed HT (e.g. 0.42)
        
        Normalised to HT timepoint 1 or most recent timepoint
        
        Normalised to hemaglobin conc. (Abs@415 nm)
        
        Weak but significant influence of HT on DBS
      - DBS validated for measurement of adalimumab
        
        DBS has PK potential
    - - https://www.fda.gov/media/70858/download
      - Section E:Validation should address, at a minimum, the effects of the following issues: storage and handling temperatures, homogeneity of sample spotting, hematocrit, stability, carryover, and reproducibility, including ISR
    - - Standards for Reporting of Diagnostic Accuracy - DBS
        
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919219/
      - Blood collection and Handling - DBS- module
        
        https://www.who.int/diagnostics_laboratory/documents/guidance/pm_module14.pdf
      - Adv/DisAvd_Description of effect (book)
        
        https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118890837.ch3
        
        Ab Stability
        
        IgA requires further study
        
        Extraction: IgM declines rapidly on storage, regardless of temp (not detectable at -20 after on month)
        
        IgG relatively stable on filter paper over 4-month period at lower temp
        
        Serology: Sera v DBS
        
        excellent corelation
      - Standardized method for Ab detection in DBS
        
        https://scihub.wikicn.top/https://link.springer.com/protocol/10.1007%2F978-1-4939-3292-4_8
        
        6 mm punch contains roughlt 6 ul serum
        
        Antibodies
        
        IgM exists as a membrane bound monomer or secreted pentamer and is the first antibody produced in response to antigen
- - - - DBS may less of a barrier to participation
    - - $2.1 billion cost of hospitalization in US between 2010-2012
        
        Owens. 2018 https://www.ajmc.com/journals/supplement/2018/examining-therapies-cidp/the-economic-burden-and-managed-care-implications-of-chronic-inflammatory-demyelinating-polyneuropathy?p=1
      - Mean cost for CIDP-related hospitalization was $70 000
      - Health plan-paid costs ~$46-66k (2/5 medical costs and 3/5 pharmacy costs, of which ~90% for IVIg therapy) - higher than MG
      - Quality of life
        
        Approx. 30% of patients will progress to wheelchair dependence if not treated
    - - rare autoimmune neuromuscular disorder - muscle weakness, reduced physical performance & increased muscular fatigue
      - Prevalence: <5 per 100 000 in EU and <1 per 500 000 in China
        
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961354/
      - Correlation between CH50 and symptoms
        
        https://www.ncbi.nlm.nih.gov/pubmed/31830679
      - 20 in 100000 in US diagnosed each year (MG foundation of America) and 14-40 per 100000 (National Organization for Rare disorders)
    - - 2019 AMR report
        https://www.alliedmarketresearch.com/intravenous-immunoglobulin-IVIG-market
        
        market estimated at $9 million in 2017 and projected $16mil by 2025.
      - 2018 market report
        https://www.grandviewresearch.com/industry-analysis/intravenous-immunoglobulin-market
        
        IVIg market - >50 primary immunodeficiency diseases including 176 rare hereditary disorders
        
        CSL IVIG = privigen