Optimization of DrugLike Properties During Lead Optimization

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Optimization of Drug-Like Properties During Lead
Optimization
Biopharmaceutic Modeling and the Role of Dose
and Formulation on Oral Exposure
Brian R. Rohrs Michigan Pharmaceutical
Sciences Kalamazoo, MI Pfizer Global RD
AAPS Workshop Parsippany, New Jersey September
19-22, 2004
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When does Formulation Impact Early Drug
Development?

• As soon as you need in vivo exposure, the drug
  delivery method has an impact
• ADME Studies
• Efficacy Models
• Toxicity Studies

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What are the Consequences of Poor Exposure?

• Ambiguous or unusable study results
• Highly variable data
• Use up scarce API
• Molecule given low priority or discontinued
  (perhaps rightly so?)

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Biopharmaceutic Models

• Many models available, from simple to very
  sophisticated (and very expensive!)
• MAD (Maximum Absorbable Dose)
• Microscopic Mass Balance Approach
• Intellipharm PK
• IDEA
• GastroPlus (ACAT)
• Models most often used for prediction of
  bioavailability, but can also use them to guide
  formulation approach to get better exposure

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Objective for Talk

• Give you a qualitative framework to understand
  the relationships between dose, solubility,
  permeability, and API particle size
• Help you to answer the questions
• Why am I getting poor exposure?
• Will formulation help me?
• What technologies should be tried?
• Keep it simple

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Microscopic Mass Balance Approach (MiMBA)

• Developed by Gordon Amidon and others at U of
  Michigan
• Qualitative method for estimating fraction
  absorbed from phys/chem data
• Simple calculation of three dimensionless values
  describing relative processes of solubilization,
  permeability, and dissolution

Oh, D-M, Curl RL, Amidon GL. Pharm Res 10(2)
1993, 264-270.
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MiMBA Schematic

• Particles introduced at beginning of intestine
• Dissolution and absorption occur as particles
  transit intestine

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Solubilization Process

• Described by Dose Number, Do
• Answers question, what fraction of my dose can
  the solvent medium hold?
• M0 Dose (mg)
• V0 Volume (ml)
• Cs Saturation Solubility (mg/ml)

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Solubilization Process (cont.)

• Variables V0 and Cs are dependent on the in vivo
  environment, V0 species dependent
• As dose number increases from 0 to 1, medium
  becomes increasingly saturated greater than 1,
  medium is saturated with solid left over

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Permeability Process

• Described by Absorption Number, An
• Ratio of absorption rate to GI transit rate
• Peff Effective permeability coefficient
  (cm/min)
• R, L Radius, Length of intestine (cm)
• Q Flow rate down GI tract (cm3/min)

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Permeability Process (cont.)

• As absorption rate gets slower than transit rate
  (An lt 1), material passes through absorption
  region before it can get absorbed
• Variables Peff, R, L, Q all species dependent
• Estimate Peff from Caco2, rat permeability, etc,
  but need correlation to species of interest
• Absorption rate constant k (min-1) related to
  Peff via geometric surface to volume ratio of
  intestine
• Peff k SA/Vol k 2/R

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Dissolution Process

• Described by Dissolution Number, Dn
• Ratio of GI residence time to complete
  dissolution time
• D Diffusivity of compound (cm2/min)
• r0 Particle radius (cm)
• Density of compound solid (mg/cm3)
• Cs, Q, R, L as previously defined

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Dissolution Process (cont.)

• As residence time exceeds dissolution time (Dn gt
  1), all material in solution and available for
  absorption
• r0 can be estimated from microscopic image
• ? function of solid (most between 1 and 1.5)
• D function of molecular size (typically6 to 8 x
  10-6 cm2/min)

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Equations Describing Dissolution and Absorption

• Calculate fraction absorbed Fabs from change in
  particle radii and change in dissolved drug down
  GI tract

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Calculate Particle Radii, Concentration and Fabs
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Bottom Line Can Map out Biopharmaceutic
Landscape

• Contour of Fabs

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Amount (mg) Absorbed Plateaus as Dose ? and Fabs ?
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Three Regions of Limited Bioavailability (An
0.6)
Where you are in the biopharmaceutic landscape
determines formulation approach for enhancing
bioavailability
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Estimating An, Dn, and Do
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Variables to Impact with Formulation

• Dose, Mo
• Solubility, Cs
• Particle size, r0
• Volume, Vo (to some extent)

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If Dissolution Limited

• Relative Dissolution Rate ? Sol/(r2)
• To speed up dissolution
• Reduce particle size
• Increasing solubility affects both Dn and Do
• Typically, if Dn gt 10, particle size reduction of
  minimum value

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Particle Radii for Dn gt 10
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If Dissolution Limited

• Relative Dissolution Rate ? Sol/(r2)
• To speed up dissolution
• Reduce particle size
• Increasing solubility affects both Dn and Do
• Typically, if Dn gt 10, particle size reduction of
  minimum value
• Exception is for high permeability, low
  solubility compouds

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Estimated Fabs for Rapid Dissolution (Dn gtgt 1)
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If Solubility Limited

• Relative Solubility ? Dose/Sol
• Enhance solubility to increase Fabs
• Strategies include ionization, surfactants,
  co-solvents, high energy solids (including
  salts), complexation agents, emulsions
• Be aware of effect of chemical potential

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Chemical Potential

• Competition for Drug Molecules

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If Permeability Limited

• Flux ? Conc Peff
• If P-gp substrate, coadminister inhibitor
• Cremophor EL
• Vitamin E-TGPS
• Polysorbate 80
• Increase Solubility
• Supersaturate at absorption site
• Be aware of chemical potential

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Influence of Chemical Potential
Yu L, et.al. Pharm Res 16(12) 1999, 1812-1817
Nerurkar MM, et.al.. Pharm Res 13(4) 1996, 528-534
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Summary

• To estimate where you are in the biopharmaceutics
  landscape, use diagrams and simple calculations
  presented here
• Reducing particle size never hurts
• When using solubility enhancers, remember that
  you can have too much of a good thing