nano-/microsuspensions: the interplay between formulation

Nicolas Darville, PhD

Nano-/microsuspensions: the interplay between

formulation properties and the injection site physiology

Long-Acting Injectables and Implantables ConferenceLeuven, BelgiumFebruary 8th, 2019

© Janssen Pharmaceutica NV – 2019

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The complex IM flip-flop pharmacokinetics exemplified

Objectives: a mechanism-based i.m. absorption model for LAI suspensions

Why considering the LAI formulation – physiology interface?

The local (i.m.) host response and its impact on the drug release

Bottom-up definition of the structural model

Acquiring the model parameters (in vivo/in vitro)

Concluding remarks

Outline


Many challenges, often relating to complex pharmacokinetics:

Poorly understood and to be solved ad hoc, often by trial and error, delaying development time lines and increasing costs

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The long way to a long-acting...

2. Multi-phasic plasma conc.–time profiles driven by slow systemic input rate (= flip-flop PK)

1. Convergence of plasma profiles & identical drug input rates (T1/2)despite varying PSD

3. Formulation effects with ‘fixed’ particle sizes- Injection volume

- Formulation strength

- Formulation composition (i.e. stabilizing excipients)


Particle size is not the only driver for the IM release from LAI suspensions:

Con

cent

ratio

n, n

g/m

L

0 1000 2000 3000 4000 5000 6000

0.1

0.5

1.0

5.0

10.0

TRTB_F013ATRTC_F13BTRTD_F13CTRTE_F13DTRTF_F011

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Modified Noyes-Whitney equation

The complex flip-flop pharmacokinetics exemplified

PP1M concept 1

PP1M concept 2

PARTICLE SIZE DISTRIBUTION OBSERVED PLASMA PK

PREDICTED PLASMA PK



Time, h

Inpu

t rat

e, m

g/h

0 500 1000 1500 2000 2500 3000

0.0

0.01

0.02

0.03

0.04

0.05

Deconvoluted input rate

BCDE

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Modified Noyes-Whitney equation


PP1M concept 1

PP1M concept 2

PARTICLE SIZE DISTRIBUTION OBSERVED PLASMA PK

DECONVOLUTED INPUT RATE



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OBSERVED PLASMA PK

Black box???

1 Reference:- Samtani et al. (2009). Clin. Pharmacokinet. 48(9): 585–600

EMPIRICAL (NON MECHANISTIC) ABSORPTION MODEL1


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Objectives: a mechanism-based i.m. absorption model

To create a translational model that allows for mechanism based

predictions of in vivo PK, based on measurable in vitro and in vivo data:

1. Bottom-up development of model-based framework

2. Acquiring in vitro and in vivo input data

3. Establish a (translational?), mechanism-based PK model

for LAI suspensions, in the rat


In vivo formulation performance of LAIs depends on multiple variables1:

Deeper understanding of the factors influencing the in vivo formulation

behavior and performance:

– Allow for in vitro assays/in silico models with increased biorelevance and predictive capacity

– Form the basis for stepping away from empirical PK models in favour of mechanism-based models

– Inform the design of ADME/TOX studies with LAIs

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Why considering the LAI formulation – physiology interface?

1 References:- Ballard (1968). J. Pharm. Sci. 57(3): 357–378 - Hirano et al. (1981). Chem. Pharm. Bull. 29(3): 817–827 © Janssen Pharmaceutica NV – 2019

The i.m. or s.c. administration of LAI suspensions induces a localized

injection site reaction1:

– Acute inflammatory reaction induced by damage to i.m./s.c. tissues during

administration (e.g. needle tract trauma, vehicle irritation, ...)

– Chronic response due to persistence of foreign (non-self) material within

biological matrix:

Universal, no matter how “biocompatible” or biodegredable substance is

Nature/rate/extent of response varies with formulation / physiology

Often characterised by confinement (“encapsulation”) to limit the spreading

, and macrophagic infiltrates to process/eliminate the foreign material

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The local host response and its impact on the drug release

1 References:- Zuidema et al. (1988 and 1994). Int. J. Pharm. 47: 1–12 and 105: 189–207- McDowell and Medlicott. (2012). Long Acting Injections and Implants, Springer US, pp. 57–71

Mechanistic consideration: influence on drug release/absorption?


The i.m. injection site reaction to LAI suspensions is characterized by

macrophage infiltration1:

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M: skeletal muscle; IS: interstitium/connective tissue; A: artery; V: vene; N: nerve; F: adipose tissue; I: cellular infiltration within depot; *: LAI formulation depot

1 References:- Darville et al. (2014). J. Pharm. Sci. 103(7): 2072–2087- Darville et al. (2015 and 2018). Toxicol. Pathol. 44(2): 189–210 and 46(1): 85–100 © Janssen Pharmaceutica NV – 2019

Increasing depot porosity (interfacial surface area) over time: e.g. PP1M, PP3M, RPV-LA

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Mechanistic consideration: changing physical characteristics!

Suspension aggregate:

low SA

Depot cellularization increases SA


Phagocytosis and intracellular relocation/accumulation of LAI formulation (in the rat)1: e.g. PP1M, PP3M, RPV-LA

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Mechanistic consideration: fate of intracellular (pro)drug crystals?

1 References:- Darville et al. (2014). J. Pharm. Sci. 103(7): 2072–2087


Intracellular compartment becomes the major site of dissolution/drug release (in the rat)1: e.g. PP1M: prodrug conversion colocalized with infiltrating macrophages (in rat)

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1 References:- Koppen et al. (2016). 3rd NVMS–BSMS Conference on Mass Spectrometry- Darville et al. (2016). J Control. Release 230: 95–108 © Janssen Pharmaceutica NV – 2019

Theoretical concept based on empirical (quantitative) histopathology vs. PK correlation and POP-PK model based hypothesis testing:

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1 Reference:- Darville et al. (2016). J Control. Release 230: 95–108


Proposed structural model*: dual (parallel) systemic input for: i) free extracellular dissolution (phys-chem driven) ii) release from macrophage cmt. (i.e. modulation by host response)

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*See also next lecture by Dr. Erno Van Schaick: Towards a generic, mechanism-based model to predict in vivo PK behaviour for LAI nano-/microsuspensions


Model input: plasma pharmacokinetics and central disposition

– i.v. and i.m. dosing of immediate release formulation (solution) in rats to obtain the systemic absorption and disposition kinetics of the active compound1.

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1 Reference:- Darville et al. (2016). J Control. Release 230: 95–108

• NCA1 or POPPK1 analysis to derived PK parameters, incl. Ka (i.m. fast first-order absorption rate constant), to describe the flip-flop PK of the parent once absorbed


Model input: nano-/microparticle (sphere) dissolution rate

– Combination of particle size distribution (and derived specific surface area estimations) and (biorelevant) in vitro intrinsic dissolution rate*

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• Use in vitro intrinsic dissolution rate* and specific surface area to estimate the net dissolution rate of the (pro)drug particles (i.e. dispersed extracellularly)

*See also poster by Vy Nguyen et al.: Intrinsic dissolution rates of rilpivirine in biorelevant medium and formulation vehicle: The impact of type and concentration of different stabilizing agents © Janssen Pharmaceutica NV – 2019

Model input: in vivo macrophage-mediated drug release rate

– Quantification & modeling the macrophage infiltration (i.e. fraction of the dose to dissolve/convert within, and be released from, macrophages)1

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• Relationship observed btw amt. phagocytosed and plasma conc.1

• ASSUMPTION: drug input rate is proportional to amt. phagocytosed

• Rate of infiltration is relatively independent of formulation1

1 References:- Darville et al. (2015 and 2018). Toxicol. Pathol. 44(2): 189–210 and 46(1): 85–100


Model input: in vivo macrophage-mediated drug release rate

– In vitro estimation of the apparent in vivo drug release rate

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• Obtained from measured conc. of active compound in extracellular acceptor compartment containing surfactant-free biorelevant medium, as function of time, normalized for effective cell density and intracellular (pro)drug load


Concept of local pathophysiology modulating the exposure only recently started to get

traction within the LA community, leading to mechanistic studies with advanced LAIs

Introduction of complex drug delivery systems in complex/reactive biological

matrices leads to interactions at the formulation – physiology interface, including

an injection site reaction, which can modulate the drug release/absorption

Knowledge of in vivo disposition can inform the design/development of more

predictive in vitro & in silico models, possibly assisting with establishing IVIVC and

informing the LAI development in the future

Present work formed the basis for first simulation attempts with PP1M/PP3M in the rat

(see next lecture by Dr. Erno Van Schaick) and shows the potential for the mechanistic

model to predict in vivo profiles of LA suspensions based on measurable in vitro

and in vivo parameters

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Concluding remarks


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Acknowledgements


MAIL TO: [email protected]

Thank you

Long-Acting Injectables and Implantables ConferenceLeuven, BelgiumFebruary 8th, 2019


nano-/microsuspensions: the interplay between formulation

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