APS - Progress within the IMI OrBiTo project – predictive tools for oral biopharmaceutics
GSK Stevenage
Development of the compound database
Tuesday 13th May 2014
Kristin Lacy, Alison Margolskee,
WP4 Objectives–within OrBiTo
•
Refine existing in silico mechanistic tools to improve
absorption modeling
–
Define the gaps in the models
–
Propose tools to calculate model performance
–
Change the inputs to the models
Amin Rostami and Xavier Pepin
2014-05-13
g
p
–
Change the algorithms to better reflect
biology and drug formulation behaviour
–
Monitor performance
Requirements for the OrBiTo compound database
•
Be novel (capture EFPIA data)
•
Be secure, accessible to all partners
•
Data capture offline with standard
tools
•
Be searchable
•
Feasibility to selectively blind some
Amin Rostami and Xavier Pepin
2014-05-13
•
Feasibility to selectively blind some
fields
•
Allow interaction whilst maintaining
full or partial anonymity
•
Be flexible to allow new fields to be
captured
OrBiTo Database – How does it work?
Amin Rostami and Xavier Pepin
2014-05-13
1.
Data gathering using Excel
Plug-in developed by Simcyp
XML File
2.
An XML file is generated containing
the data collected in the Excel plug-in
3.
XML file is imported into the
OrBiTo database which is
stored within the ‘Cloud’
4.
Users query the database using
the ‘OrBiTo Query Language’
5.
Data is downloaded from the database
and the Excel plug-in is re-populated with
the downloaded data.
•
Backups of the database are taken once a week so if any
failures were to happen then we would be able to rebuild the
database.
OrBiTo Database – Backups
•
All backups are stored within the ‘Cloud’ and are kept for 90
OrBiTo Database – How/when was it built ?
Amin Rostami and Xavier Pepin
2014-05-13
•
August
2012
: Pre-project discussions started between Sanofi
& Simcyp to decide what type of data, metadata was to be
captured and in what units and format. A decision about
how the data would be collated was also made during this
time (Excel plug-in).
Data type Metadata Value Unit Format Comments For what purpose Minimal dataset
Main challenge with the drug Indicate the main challenge from picklist and also free text Text Drop down menu 0 Important pKa Indicate basic"B" of acidic "A" nature + method of obtention (calculated or measured, indicate batch number used) no unit
n / 3 matrix [n values rounded to +/- 0.1 / "A" for acid or "B" base/
Method of obtention]
Indicate all the pKas of the drug Calculate ionization, distribution, permeability vs pH Compulsory
f T l l h diff i ffi i Molecular weight of active moiety None g.mol-1 1 value +/- 1 g/mol For blinding purposes the use of ranges could be made.
Proposal to round it to +/- 1 g/mol
To calculate the diffusion coefficient (dissolution rate) +/- 1 g/mol Compulsory API Log P Shake flask, pH-metric, pH-UV, HPLC, CE no unit (log ratio) [1 value +/- 0.1 / Method of
obtention = DDM5] log P = Log D of the unionized species
Anticipation of many partition properties with/through biological membranes. Anticipation of solubility in micellar systems, use in the ACAT model for absorption scaling factors
Compulsory
API Log D = LogP @pHn Shake flask, pH-metric, pH-UV, HPLC, CE no unit (log ratio)
n / 3 matrix (n pH values / n Log D values +/- 0.1/Method of obtention = DDM5]
Choose as many log D as different types of ionized species based on the pKas. Choose pH rationnaly, i.e. pH1 = pKa1-2 ; pH2 = (pka1+pKa2)/2...etc or best reconstruct full lipophilicity profile
QSAR modeling, anticipation of many partition properties with/through biological membranes. Anticipation of solubility in micellar systems
Compulsory
Apparent API permeability through membrane (Bi-directional)
Indicate membrane nature (strain of cells or artificial) + drug concentration in donor+ direction or transport + pH in donor + pH in acceptor + recovery + inhibitor nature + inhibitor concentration + BSA concentrations in donor + value
nm/s
n/14 matrix [n values Papp (+ - 0.1 nm.s-1) / membrane nature = DDM1 / drug concentration in donor (µM)/ "A2B" or "B2A"/ pH in donor + - 0.1/ pH in acceptor + -0.1/ recovery (+ - 1%)/ inhibitor name / inhibitor concentration (µM)/ BSA concentration in donor (%)/BSA concentration in acceptor (%)/ Agitation rate (rpm)/ type of agitation = free text/ Size of Unstirred Water Layer(µm)/other info = free text/ Cross reference to method PxMn]
Need to define a list of reference drugs to be tested at a certain concentration in the apical compartment to serve as reference for the Papp measurements coming from different labs, provide the Papp of these "reference drugs" in a separate table with open name for the drug but similar format indicated in format column
Use to run/ validate in silico tools