The optimal use of biorelevant media & simple modelling for the prediction of in-vivo oral behaviour
James ButlerProduct 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 humanHigh variability with a few replicates: difficult to interpretOutcomes 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)
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I Good solubility and permeability
IIGood permeability, poor solubility
IIIGood solubility, poor permeability
IVPoor solubility and permeability
BCS/DCS plot with human jejunal permeability and aqueous dose solubility ratio as axes
IIa (dissolution rate limited)
IIb (solubility limited)
Using jejunal solubility, typically FaSSIF@37°C
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IVPoor solubility and permeability
DCS plot with human jejunal permeability and aqueous dose solubility ratio as axes
I/IIa/III (all potentially dissolution rate limited!)
IIb (solubility limited)
Typically in FaSSIF@37°C
Why? –
dissolution rate is related to solubility, not dose/solubility ratio.
Use a “target particle size”
to express this risk
SLAD
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 solubilityHIF solubilityFaSSIF
(several versions now reported in the literature!)
Permeability–
Correlate to obtain an estimated human jejunal
permeabilityFraction absorbed data (if permeability is low)Rat perfusionCell 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.
250 500 1000 10000 100000D/S in FaSSiF@37ºC
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P eff
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/sec
x10
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I IIa
III IV
Digoxin
IIbNeutral, max. dose 0.5mg,
Fassif
solubility 17μg/mL,
Estimated permeability 0.9x10-4cm/sec
BCS III, DCS III
Recommended max particle size: 10µm(X50
), 32µm(X90
),
80-90% fraction absorbed
100 micron particles only 39% relative bioavailability to oral solution
9 & 13 micron mean particle formulations both bio-equivalent to oral solution
250 500 1000 10000 100000D/S in FaSSiF@37ºC
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I IIa
III IV
Mefenamic
acid
IIb
Weak acid, Insoluble across most of physiological range, max. dose 250mg
Fassif
solubility 30μg/mL
(pH 6.5), increases with pH
Estimated permeability 14x10-4cm/sec
BCS II, DCS IIA,
Recommended max particle size: 13µm(X50
), 42µm(X90
),
Borderline for being solubility limited
Bioavailability is known to be highly particle size/dissolution rate dependant
Reported issues with variable efficacy of some products. Some commercial products show a food effect, others don’t
250 500 1000 10000 100000D/S in FaSSiF@37ºC
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Pef
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Hum
ans c
m/s
ec x
10-4
I IIa
III IV
IIb
Griseofulvin
Neutral, highly insoluble, max. dose 1000 mg
FaSSIF
solubility 19μg/mL
Estimated permeability 8.7x10-4cm/sec
BCS II, DCS IIB,
Highly solubility limitedRecommended max particle size: 11µm(X50 ), 34µm(X90 ),
Solid dispersion approach used for a commercial oral product (GRIS-
PEG) with enhanced bioavailability
Less than linear increase in exposure with increasing dose
With or without with the bio-
enhanced approach, sizable food effects are seen
Solubility estimation - Is FaSSIF solubility a reasonable estimate of actual human intestinal solubility?
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
+/- Standard deviation
Reasonable estimate for most unionised drugs, but more variable for acids/bases
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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
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P eff
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I IIa
III IV
Ibuprofen
Troglitazone
HO-221
Atovaquone
Halofantrine
Digoxin
Mefenamic acid
Carvedilol
IIb
Amprenavir
Itraconazole
Etravirine
Nitrendipine
Aprepitant
Fenofibrate
Megestrol Acetate
Paracetamol
Furosemide
Danazol
IR oral drug products and BCS
When are IVIVRs
likely?–
The established view (and a regulators view?):
BCS 1 – IVIVRs unlikely: gastric emptying controls oral absorption
BCS 3 – IVIVRs unlikely as permeability controls oral absorption
BCS 4 – IVIVRs possible on a case by case basis only
BCS 2– IVIVRs likely to be possible
Provided dissolution is rapid
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 ratesolubility, 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
Hum
an je
juna
lper
mea
bilit
y
DCS I In-vitro sensitivity > in-vivo sensitivity
DCS IIIIVIVRs unlikely
DCS IVIVIVRs from simple in-vitro methods unlikely, but may be possible with complex in-vitro methods /modelling
DCS IIa* IVIVRs from simple in-vitro methods likely to be possible
DCS IIbIVIVRs from simple in-vitro methods less likely, may need to use more 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 -
calibrated cell line, whole body radiolabelled study
etc, but method must follow regulatory guidance
Predicted human jejunal permeability, usually
predicted from a from cell line measurement or from
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 in-
vitro 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?