Basics of biopharmaceutics and overview of work approaches...Basics of biopharmaceutics. What is the...

Dr. Simone HansmannFrankfurt/Main April 2019

APV course “Biopharmaceutics meets Formulation Development”

Basics of biopharmaceutics and overview of work approaches

1. What is the scope of my work?

2. What is the input and output of my work?

3. What info do I need for my daily work?

4. Which tools do I use on a daily basis and how do they work?

5. What do I think is the important results for the formulator?

6. Where is the value for a formulation scientist?

7. Pitfalls to avoid?

Basics of biopharmaceuticsAgenda

Biopharmaceutics meets Formulation Development | 11/12. April 20192


Basics of biopharmaceuticsWhat is the scope of my work?

De-risk compound selection

Investigate the CMC-focused developability of compounds

Investigate absorption characteristics in special patient populations

Increased stomach pH

Food effects

Predict the absorption behavior of development candidates in preclinical species

in humans

Supportformulation development

Early identification of parameters possibly critical to absorption

Life-cycle management

CoE Translational Biopharmaceutics

@ Merck Coupling in vitro and in vivo data with an in silico

model

Example 1 in part 2

Example 2 in part 2


Basics of biopharmaceuticsWhat is the scope of my work?

- Identify operational ranges for formulation development

- Support estimation of likelihood of success of (relative) bioavailability or bioequivalence studies and support waiver of bioavailability and bioequivalence studies.

- Prediction of the effect of food or gastric pH-modifying agents on drug absorption.

- Prediction of oral drug absorption to support the First-in-Human dose predictions by integrating all relevant preclinical information into the model.

- Support development/selection of First-in-Human formulation

- Identification of parameters critical for drug absorption

- Early prediction of absorption and support decision-making on CMC development strategy for exposure enhancement

- Support development of mitigation strategies for compounds with potential dissolution/solubility liability

Provides early (absorption) risk assessment

De-risk and support compound selection

PHASE 0 Clinical phase and LCMDiscovery

Example 1 in part 2

Example 2 in part 2

Innovation Day 2017 - Darmstadt5

Basics of biopharmaceuticsWhat is the input and output of my work?

Absorption

SolubilitypH dependent

biorelevant

PermeabilityPassive permeability

Substrate of influx or efflux transporter

Formulation

PrecipitationMay precipitation upon

transfer from the stomach into the SI limit the extent

of absorption?

DoseIs the absorption dose-

linear?

Particle size/dissolution

Particle size

Particle morphology

Particle density

Phys.-chem ParametersMW, log P, log D, diffusion coefficient

Physiology



The easiest way of performing a biopharmaceutical classification of a development compound is based on the compound`s solubility and effective permeability according to the Biopharmaceutics/Developability Classification System.

The Biopharmaceutics Classification System (BCS) according to Amidon et al.

The Developability Classification System (DCS) according to Butler and Dressman



• Permeability• PK parameters (Vss; CL; FPM)D

MP

K

• Physchem (log P/D; pKa) • Solubility• PSD A

nal

ytic

sC

PD

API Characteristics and formulationparameters

• Precipitation• Formulation characteristics

Generation and Preparation of API data

Integration of data into the PBPK model

Interpretation and presentation of results

Mathematical relationship between the plasma

concentration and the time


Basics of biopharmaceuticsWhat info do I need for my daily work?

+

System parameters

Mathematical relationshipPredicted PK of the drug: Absorption,

distribution, elimination

Drug and formulation parameters

01010001110100101001001101001011100010101010001010111100100110101010101001110100101011001010100111110001010110100011010101010100010110110100101010010101010101010101100101010010


Basics of biopharmaceuticsWhich tools do I use on a daily basis?

pH0 1 2 3 4 5 6 7 8

Con

cent

ratio

n (µ

g/m

L)

0

200

400

600

800

1000

1200

1400

1600

1800

2000

pH0 1 2 3 4 5 6 7 8

Con

cent

ratio

n (µ

g/m

L)

0,1

1

10

100

1000

10000

Determination pH dependent solubility In-vitro Dissolution in standard or biorelevant media XRPD

In-vitro transfer experiments

Standard set-up

Small scale set-up



For more information, please see:

Jede et al., 2018: In-line derivative spectroscopy as a promising application to a small-scale in vitro transfer model in biorelevant supersaturation and precipitation testing

Jede at al., 2019: Automated small-scale in vitro transfer model as screening tool for the prediction of in vivo-dissolution and precipitation of poorly solubles

12

The Advanced Compartmental Absorption and Transit model in GastroPlus

Unreleased

Undissolved

Dissolved

Enterocytes

Luminaldegradation

Excr

etio

n

Hepatic artery

Systemic circulation

1st

compartment2nd

compartment

Stomach Duodenum Jejunum 1 Jejunum 2 Ileum 1 Ileum 2 Ileum 3 CaecumAscending

colon

Portal vein

Liver

Gall bladder


Basics of biopharmaceutics


Basics of biopharmaceuticsHow do the tools work?

Is precipitation potentially a limiting factor for the oralabsorption? ( weak bases)

Yes, this drug may be prone to precipitation

Is absorption dissolution-rate limited? Can micronization( increase DR) compensate for low solubility? This drug does not exhibit DR-limited absorption behavior.Decreasing the particle size most likely does not increaseabsorption.

Do we expect dose-linear absorption in humans? Unfortunately, this drug may exhibit dose-dependent (non-linear) absorption. Even at low doses, absorption may beincomplete.

Is absorption potentially solubility-limited? Unfortunately, this drug is predicted to exhibit a solubility-limited absorption behavior. Only by increasing solubilitysubstantially, “acceptable” absorption may be reached.

Perc

ent

abso

rbed

How does permeability impact absorption? ( Pgp) This estimation can serve as surrogate for Pgp-mediatedefflux. The effect of variations in permeability on the absorptionof this drug is predicted to be rather moderate.

Formulations tested: Solution, capsule

(other formulations, such as suspensions and tablets, also feasible)

“Baseline simulation”Applying measured values for solubility and Peff and GastroPlusdefault values (unless other date is available) for precipitationtime, dose, and particle radius “reference values”


Basics of biopharmaceuticsWhat do I think is the important results for the formulator?

Iterative predict/learn/confirm cycle – and then use the model for prediction of an untested scenario

2

3

1

Learn• Why do simulations not

match observed data?

• Generate new hypothesis/hypotheses

Confirm• Can we describe the

observed PK data?

• Verify hypothesis/hypotheses

Predict• Use parameters “as is” for

simulations

• Simulate known scenario (e.g., preclinical PK data)

… and then apply!

Translational biopharmaceutics


Basics of biopharmaceuticsWhat do I think is the important result for the formulator?

De-risk the formulation development process by identification of operational ranges for formulation development and determine the impact on drug exposure− changes in release mechanisms (e.g., immediate release (IR) vs. modified release (MR))− exchange of excipients− reformulation in the course of life cycle management

Support of the development or selection of interim and commercial formulations by understanding failures of formulations, develop mitigation strategies, and predict untested scenarios − Facilitates decision-making− Streamlines the formulation development process, saves time and resources− Strengthens the interface co-operation


Basics of biopharmaceuticsPitfalls to avoid?

Confidence

High

Medium

Low

Confidence

High

Medium

Low

Confidence

High

Medium

Low

The basic principle of each model:

Trash in - trash out

Dr. Simone HansmannFrankfurt/Main April 2019

APV course “Biopharmaceutics meets Formulation Development”

Biopharmaceutic work approaches in pharmaceutical industry

1. Examples of standard work approaches How do you combine and apply the tools in detail?

2. Interfaces between the functions

Biopharmaceutic work approachesAgenda


Example 1 Standard work approach –Drug Discovery

20 Biopharmaceutics meets Formulation Development | 11/12. April 2019

26 potential candidates for the exploratorydevelopment phase:

How to select a suitable compoundwith favorable properties forfurther development?

Examples of standard work approaches

Project challenge

Work approach

Conduct a CMC-focused developabilityassessment for all 26 compounds andestimate potential impact of solubility,precipitation, particle size, dose, andpermeability on absorption in humans.

Support the drug product development byidentifying compounds with unfavorable CMCproperties.

Biopharmaceutic work approachesExample 1: CMC-focused

developability assessment

Example 1: CMC-focused developability assessment


Basics of biopharmaceuticsHow do the tools work?

Is precipitation potentially a limiting factor for the oralabsorption? ( weak bases)

Yes, this drug may be prone to precipitation

Is absorption dissolution-rate limited? Can micronization( increase DR) compensate for low solubility? This drug does not exhibit DR-limited absorption behavior.Decreasing the particle size most likely does not increaseabsorption.

Do we expect dose-linear absorption in humans? Unfortunately, this drug may exhibit dose-dependent (non-linear) absorption. Even at low doses, absorption may beincomplete.

Is absorption potentially solubility-limited? Unfortunately, this drug is predicted to exhibit a solubility-limited absorption behavior. Only by increasing solubilitysubstantially, “acceptable” absorption may be reached.

Perc

ent

abso

rbed

How does permeability impact absorption? ( Pgp) This estimation can serve as surrogate for Pgp-mediatedefflux. The effect of variations in permeability on the absorptionof this drug is predicted to be rather moderate.

Formulations tested: Solution, capsule

(other formulations, such as suspensions and tablets, also feasible)

“Baseline simulation”Applying measured values for solubility and Peff and GastroPlusdefault values (unless other date is available) for precipitationtime, dose, and particle radius “reference values”


Examples of standard work approachesBiopharmaceutic work approaches


Parameter Sensitivity Analysis compound 1

Precipitation time of compound 1 [sec]

Reference solubility of compound 1 [mg/mL]

Effective permeability of compound 1 [*10-5 cm/s]

Dose of compound 1 [mg]

Mean drug particle radius of compound 1 [µm]

Particle size

reduction as potential mitigation strategy for poor absorption




Parameter Sensitivity Analysis compound 1Parameter Sensitivity Analysis compound 2

Precipitation inhibition

as potential mitigation strategy for poor absorption









Parameter Sensitivity Analysis compound 3

Increasing solubility (e.g., amorphization)

as potential mitigation strategy for poor absorption







Biopharmaceutic work approachesExamples of standard work approaches

1) Identification of compoundswith “acceptable” CMCproperties: 17/26

2) Alignment with quantitativepharmacology depeartmentto further select compounds,based on (predicted) PKprofile: 4/17

3) Final identification of one EDcandidate was possible

In silico-based Developability Assessment: Actively contributing to compound selection


Compound 1 Compound 2 Compound 3 Compound 4

Standard work approaches -Drug Development



The project of compound M was in Ph1,which was conducted using aPowder-in- Capsule formulation; Ph II tobe run with a tablet formulation:

How will the clinical PK from the tabletperform compared the PK of the powder-in-capsule formulation?

Is a dose-adjustment needed?

Project challenge

Work approach Predict exposure of compound M from tablet

formulation Support decision as to whether or not a dose

adjustment is needed for Ph2

Example 2: support exposure predictions

for formulation bridging


1. Model building

• Use available phys-chem and clinical data to build a GastroPlusTM model. Clinical data derive from a single ascending doses study.

2. Model verification (“predicting the known”)

• Using the model which was previously set up and predict PK of multiple ascending doses study.

3. Model application (“predicting the unknown”)• Predict exposure of compound M for the powder-in-capsule formulation in relative BA study

• Predict exposure of compound M for the tablet formulation in relative BA study

As soon as clinical data are available:

• Compare predicted and observed PK “accuracy” of predictions and summarize implications for comparable projects in the future




Work approach


Comparable exposure of both formulations predicted no dose adjustment for Ph2 necessary


AUC(0-12) [ng/mL/h] ratio (tablet/PiC) cmax [ng/mL] ratio Tmax [h]

1.03 0.96 Capsule Tablet0.8 0.9



Tablet

Model application

Powder-in-capsule



predicted observed ratio(pred/obs)AUC(0-12) (tablet/PiC) 1.03 0.85 1.20

cmax (tablet/PiC) 0.96 1.02 0.94Observed: Geometric mean



Comparison to clinical data Powder-in-capsule Tablet


Biopharmaceutic work approachesInterfaces between the functions

Bio-pharm

Regulatory

ADME

DSPhyschem

PKClinics

DPFormulation

Physiology

TranslationalBiopharmaceutics

„Progressing Merckcompounds from research into the clinics

and beyond“

Research Pharmaceutics Scientist (CoE Translational Biopharmaceutics)Healthcare R&D | CPD | Pharmaceutical Technologies

Merck KGaAFrankfurter Straße 25064293 Darmstadt

[email protected]

Lead Center of Excellence (CoE) Translational BiopharmaceuticsHealthcare R&D | CPD | Pharmaceutical Technologies


[email protected]

Dr. Simone HansmannDr. Christian WagnerPhD student (CoE Translational Biopharmaceutics)Healthcare R&D | CPD | Pharmaceutical Technologies


[email protected]

Christian Jede

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