Nano-/microsuspensions: the interplay between formulation ...
Transcript of 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
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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)
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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
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Particle size is not the only driver for the IM release from LAI suspensions:
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
The complex flip-flop pharmacokinetics exemplified
PP1M concept 1
PP1M concept 2
PARTICLE SIZE DISTRIBUTION OBSERVED PLASMA PK
DECONVOLUTED INPUT RATE
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Particle size is not the only driver for the IM release from LAI suspensions:
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The complex flip-flop pharmacokinetics exemplified
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
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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?
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The i.m. injection site reaction to LAI suspensions is characterized by
macrophage infiltration1:
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The local host response and its impact on the drug release
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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The local host response and its impact on the drug release
Mechanistic consideration: changing physical characteristics!
Suspension aggregate:
low SA
Depot cellularization increases SA
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Phagocytosis and intracellular relocation/accumulation of LAI formulation (in the rat)1: e.g. PP1M, PP3M, RPV-LA
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The local host response and its impact on the drug release
Mechanistic consideration: fate of intracellular (pro)drug crystals?
1 References:- Darville et al. (2014). J. Pharm. Sci. 103(7): 2072–2087
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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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The local host response and its impact on the drug release
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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Bottom-up definition of the structural model
1 Reference:- Darville et al. (2016). J Control. Release 230: 95–108
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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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Bottom-up definition of the structural model
*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
© Janssen Pharmaceutica NV – 2019
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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Acquiring the model parameters (in vivo/in vitro)
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
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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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Acquiring the model parameters (in vivo/in vitro)
• 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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Acquiring the model parameters (in vivo/in vitro)
• 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
© Janssen Pharmaceutica NV – 2019
Model input: in vivo macrophage-mediated drug release rate
– In vitro estimation of the apparent in vivo drug release rate
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Acquiring the model parameters (in vivo/in vitro)
• 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
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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
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MAIL TO: [email protected]
Thank you
Long-Acting Injectables and Implantables ConferenceLeuven, BelgiumFebruary 8th, 2019
© Janssen Pharmaceutica NV – 2019