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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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

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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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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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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?