The optimal use of biorelevant media
& simple modelling for the prediction
of in-vivo oral behaviour
James Butler
Product Development
GlaxoSmithKline
What level of complexity is needed for adequate
prediction of in-vivo behaviour?
The application of simple biopharmaceutics
modelling to early oral formulation development
Desired knowledge:
– Are drug & formulation properties adequate for good
exposure/low variability in early human studies?
What drug particle size?
Is a bio-enhancement (solubilisation) strategy needed?
– If so, which approach to choose?
Developing multiple formulations is inefficient
– During dose escalation, above what dose is loss of
linearity in AUC/dose likely?
May be similar to the dose above which large solubility-related
food effects occur.
Available methods for the prediction of likely oral
in-vivo performance in humans
Animal PK data
– Often trusted more than alternatives, but….
Needs justification (minimise animal use)
Not always predictive of human
High variability with a few replicates: difficult to interpret
Outcomes may be dose dependant
– Safety assessment (higher doses) and FTIH may need different formulation
approaches
Models and simple measurements
– Simple: solubility & permeability data, BCS, Maximum Absorbable Dose
– Complex: Commercially available software models such as Gastro-Plus
Although the sensitivity analysis tool within Gastro-Plus is conceptually simpler
Dissolution methods
– Simple: standard pharmacopoeial methods optionally with biorelevant
media
– Complex: non-pharmacopoeial methods: dynamic media transfer methods,
TNO-TIM-1, IFR-DGM, dissolution/cell-line combinations, etc
Developing a modified classification system
BCS – a regulatory tool
– Conservative, efficacy and patient safety in mind
When is there no bio-inequivalence risk?
– Useful in late development and post-launch
DCS – a developability tool
– Aim: realistic, product development issues in mind
What factors are likely to control the extent of oral absorption?
– Permeability, solubility, dissolution rate
– Useful in evaluating new drug candidates (early
development)
Predicted Peff in Humans cm/sec x10-4
Dose/solubility ratio
250
500
1000
5000 10000
Using jejunal solubility,
typically FaSSIF@37°C
10
I
Good solubility
and permeability
IIa
II
(dissolution
rate limited)
Good permeability,
poor solubility
IIb
(solubility
limited)
1
III
IV
Good solubility, poor
permeability
Poor solubility and
permeability
0.1
BCS/DCS plot with human jejunal permeability and
aqueous dose solubility ratio as axes
100000
Dose/solubility ratio
250
500
1000
5000 10000
100000
Predicted Peff in Humans cm/sec x10-4
Typically in FaSSIF@37°C
SLAD
10
IIb
(solubility
limited)
I/IIa/III (all potentially
dissolution rate limited!)
1
Why? – dissolution rate is
related to solubility, not
dose/solubility ratio.
Use a “target particle size” to
express this risk
IV
Poor solubility and
permeability
0.1
DCS plot with human jejunal permeability and aqueous
dose solubility ratio as axes
Some key features of the DCS
Solubility limited absorbable dose (SLAD):
– Assumes a 500ml volume available for drug dissolution.
– Peff >1x10-4 cm/sec assumed to proportionally increase the effective volume
available for dissolution of highly permeable drugs
– Represents the dose above which absorption is solubility limited. i.e. beyond
this:
– linear exposure/dose response may be lost
– Solubility related food effects are likely
– Reducing particle size alone cannot achieve complete absorption
Recommended particle size
– Derived from “dissolution number” equation
– Approach: set target dissolution number to 1, solve the equation for particle
diameter, use this as the target x90.
Dn concept from Oh et al, Pharm Res 1993 10 (2) 264-270
Solubility and permeability estimations
Solubility
– Use best estimate available of (fasted) intestinal solubility
HIF solubility
FaSSIF (several versions now reported in the literature!)
Permeability
– Correlate to obtain an estimated human jejunal permeability
Fraction absorbed data (if permeability is low)
Rat perfusion
Cell line (CACO-2, MDCK)
In-silico/part in-silico models
What is the most significant solubility to estimate for early
development?
Early clinical studies are almost invariably performed in the fasted
state.
– Fasted state usually “worst case” for low solubility compounds
Fasted state gastric residence times are relatively short and variable
compared to the small intestine.
Gastric solubility:
– of greatest importance for poorly soluble weak bases.
even for these, having adequate intestinal solubility offers insurance
against PK variability.
Therefore, in a simple oral absorption model with a single solubility
input, fasted intestinal solubility is most relevant.
250
Predicted Peff in Humans cm/sec x10-4
D/S in FaSSiF@37ºC
10
500
I
1000
5000 10000
100000
IIa
IIb
Neutral, max. dose 0.5mg,
Fassif solubility 17μg/mL,
Estimated permeability
0.9x10-4cm/sec
BCS III, DCS III
1

Digoxin
III
Recommended max particle size: 10µm(X50), 32µm(X90),
IV
80-90% fraction absorbed
0.1
100 micron particles only 39%
relative bioavailability to oral
solution
9 & 13 micron mean particle
formulations both bio-equivalent to
oral solution
Predicted Peff in Humans cm/sec x10-4
250
D/S in FaSSiF@37ºC
Weak acid, Insoluble across
most of physiological range,
max. dose 250mg
10
500
I solubility 30μg/mL (pH
Fassif
6.5), increases with pH
1000
5000 10000
100000

Mefenamic acid
IIa
IIb
Estimated permeability
14x10-4cm/sec
BCS II, DCS IIA,
Recommended max particle size:
13µm(X50), 42µm(X90),
1
Borderline for being solubility limited
III
0.1
Bioavailability is known to be highly
IVsize/dissolution rate
particle
dependant
Reported issues with variable
efficacy of some products. Some
commercial products show a food
effect, others don’t
Predicted Peff in Humans cm/sec x10-4
D/S in FaSSiF@37ºC
250
500
1000
5000 10000
100000
Neutral, highly insoluble,
max. dose 1000 mg
10
FaSSIFI solubility 19μg/mL
IIa
IIb

Estimated permeability
8.7x10-4cm/sec
Griseofulvin
BCS II, DCS IIB,
Highly solubility limited
Recommended max particle size: 11µm(X50), 34µm(X90),
1
III
Solid dispersion approach used for
a commercial oral product (GRISIV
PEG) with enhanced bioavailability
Less than linear increase in
exposure with increasing dose
0.1
With or without with the bioenhanced approach, sizable food
effects are seen
Solubility estimation - Is FaSSIF solubility a reasonable
estimate of actual human intestinal solubility?
+/- Standard deviation
Reasonable estimate for most unionised drugs, but more variable for acids/bases
Data from: Pharm Res 22 12 2005 2141-2151, Pharm Res 17 2000 183-189 & 891-894, Eur J. Pharm Sci 39 2010 15-22,
Pharm Res 26 2009 1456-1466, Pharm Res 23 2006 1373-1381, Int. J Pharm 376 2009 7-12, Pharm Res 22 2005 2141–
2151, Int J. Pharm 336 2007 302-309, Drug Met Dispos 38 2010 1407-1410 J Pharm Sci 99 2010 4525-4534, Mol Pharm 7
2010 1498–1507, J Pharm Pharmacol 62 2010 1656-1668
250
D/S in FaSSiF@37ºC
500
1000
5000 10000
100000
Predicted Peff in Humans cm/sec x10-4

Mefenamic acid

Ibuprofen
10

I


Halofantrine
IIa
Nitrendipine



Carvedilol

Aprepitant


IIb
Troglitazone

Etravirine

Paracetamol
 Itraconazole





Fenofibrate  Danazol


1





Atovaquone

Amprenavir

Megestrol
Acetate

HO-221


Digoxin
III

Furosemide
IV
0.1
DCS plot for developability assessment: Approximate position for selected drugs
 - Size control (microns+) adequate for complete dissolution in-vivo
Proven significant bioavailability advantage for:  Wet-milled/nano-milled formulations,  Solid dispersion
 Liquid filled capsule
IIa /(I/III)- dissolution rate limited, IIb/IV- solubility limited
IR oral drug products and BCS
When are IVIVRs likely?
– The established view (and a regulators view?):
Provided
dissolution
is rapid
BCS 1 – IVIVRs
unlikely: gastric
emptying controls
oral absorption
BCS 3 – IVIVRs
unlikely as
permeability controls
oral absorption
BCS 2– IVIVRs
likely to be
possible
BCS 4 – IVIVRs
possible on a case
by case basis only
In practice though….
Many BCS II drugs as IR products are difficult candidates
for IVIVR either because:
– Adequate solubility in the stomach or small intestine
means little actual in-vivo sensitivity to dissolution rate
Or:
– Drug absorption in-vivo is sensitive to multiple
interacting factors in addition to dissolution rate
solubility, supersaturation, precipitation, boundary layer diffusion
– The use of solubilising forms (e.g. salts) and formulations further
complicates these interactions
How rapidly the drug dissolves has an impact on saturatable
processes
– E.g. first pass metabolism, efflux, active uptake
DCS: a better rationale for the appropriate
use of IVIVRs for IR products?
Dose/ intestinal solubility ratio
DCS I
Human jejunal permeability
In-vitro sensitivity > in-vivo
sensitivity
DCS IIa*
IVIVRs from
simple in-vitro
methods likely to
be possible
DCS IIb
IVIVRs from simple
in-vitro methods less
likely, may need to use
more complex in-vitro
methods/ modelling
DCS III
DCS IV
IVIVRs unlikely
IVIVRs from simple in-vitro
methods unlikely, but may be
possible with complex in-vitro
methods /modelling
* Including low dose, low solubility (DCSI/III) drugs like digoxin
Biopharmaceutical Classification System
Developability Classification System
Uses minimum solubility in the pH range 1-7.5
Uses an estimate of jejunal solubility (FaSSIF or HIF)
Assumes 250ml available to dissolve the drug
Assumes 500ml available to dissolve the drug
Single class 2 box
Additional IIa/ IIb classification to distinguish
between dissolution rate and solubility limited drugs
High/low permeability cut-off is 90% fraction absorbed (FA)
(equivalent to human jejunal Peff of ~1.0 x10-4 cm/s)
Various methods used for permeability or FA -
Predicted human jejunal permeability, usually
calibrated cell line, whole body radiolabelled study
predicted from a from cell line measurement or from
etc, but method must follow regulatory guidance
in-silico estimate based upon structure and LogD
Used to support biowaivers (Class I compounds)
Used to assess developability, identify factors
limiting oral absorption, aid formulation choice
Complex versus simple
In a much more cost-aware industry, there is a desire to minimise costs
of early development.
The development of drugs with poor solubility/ poor oral absorption is a
particular challenge to “keep it simple in early development” thinking.
Complex: multiple formulation approaches developed for potential
human use, all of which are fully characterised by the best available invitro dissolution methods and animal in-vivo studies.
Simple: single formulation developed for early human studies, essential
characterisation only. Simple models (e.g. DCS, Gastro-Plus sensitivity
analysis) used to identify the most appropriate formulation and particle
size.
– With biorelevant media solubility as key input data
Conclusions
The use of biorelevant media solubility, in conjunction with a simple
classification system (DCS) to assess the developability of oral drugs
is attractive as:
– Key factors influencing drug absorption can be simply represented by a
few key parameters (SLAD and a target particle size) and visualised by
plotting position on a BCS-like 2D graph.
Tools like DCS are potentially valuable in reducing resource pre-FTIH
in rational formulation development.
Improved estimates of key input data (e.g. intestinal solubility,
permeability) are key to the reliable prospective prediction of oral
absorption.
Acknowledgements
The former “Predictive Technologies” group at GSK, in particular, Paul
Connolly & Richard Lloyd
Prof. Jenny Dressman (Uni. of Frankfurt)
Questions?