NuevasvíasdeadministracióndelTAR¿Haciadóndenosdirigimos?
José R. Blanco Hospital San Pedro – CIBIR
Logroño
Conflictos de interés
• Abbive
• BMS
• Janssen
• Gilead
• MSD
• ViiV
Limitaciones del TAR
• El TAR ha cambiado la historia natural de la infección por VIH.
• La falta de adherencia supone una limitación para el
control1,2 y la prevención de la infección3,4
• La adherencia se ve afectada por múltiples causas.
• La penetración del TAR es inadecuada en algunos tejidos.
• Las nuevas tecnologías pueden contribuir a la mejora de la
adherencia y la penetración en los tejidos infectados.
1.Millsetal.JAMA2006;2.Limaetal.JAIDS2009;3.Koenigetal.AmJPrevMed2013;4.vanderStratenetal.AIDS2016
Nanotecnología
• Podría ser la respuesta a necesidades médicas no conseguidas.
• Ofrece la posibilidad de múltiples mecanismos de acción.
• Podría maximizar la eficacia farmacológica (reducción de dosis y
de toxicidades).
• Podría transportar los fármacos de un modo optimizado a través
de las barreas biológicas.
• Podría ofrecer una biodistribución sitio-específica.
• Podría permitir una liberación farmacológica controlada y PK
dependiente del tamaño, forma y superficie.
BasadoenRuíz-Cabello.62CongresoSEFH2017
hTp://3.bp.blogspot.com/_p2ZBNGf_7w8/TUqfAda6dsI/AAAAAAAAF6I/w1OJbt7FE20/s1600/ch4_size.jpg
Nuevas estrategias frente al VIH
• Los macrófagos y las células dendríticas fagocitan partículas de diferentes tamaños.
hTp://www.revista.unam.mx/vol.13/num10/art103/-hTps://allyouneedisbiology.wordpress.com/tag/tamano-microorganismos/
Hematíes
Núcleo del macrófago
hTps://www2.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2122/notes/lymph.htm
Nuevas estrategias frente al VIH
• El tamaño de loa linfáticos limita la penetración de los fármacos.
Sanchezetal.JID2015
(2015)
Nuevas estrategias frente al VIH
• Existen recetores tisulares específicos.
Synetal.PharmacologSci2016
Curleyetal.FutureSci2017
Vías
IntradérmicaSubcutáneaIntramuscularIntravenosa
Vías
OpjcaNasalOcularRectalVaginal
Dérmicas Insjlacioneseirrigaciones Inhalatorias
Vías de administración
Vías
Oral Sublingual Tópica Parenteral
Vías
IntradérmicaSubcutáneaIntramuscularIntravenosa
Vías
OpjcaNasalOcularRectalVaginal
Dérmicas Insjlacioneseirrigaciones Inhalatorias
Vías de administración
Vías
Oral Sublingual Tópica Parenteral
Vía oral
• La más empleada
• Inconvenientes:
- Algunos pacientes tienen problemas de deglución
- Algunos fármacos tienen un sabor desagradable
- Exige una integridad digestiva, pH,…
- Existen factores que pueden influir en la biodisponibilidad
- ¿Adherencia?
2013
Vías
IntradérmicaSubcutáneaIntramuscularIntravenosa
Vías
OpjcaNasalOcularRectalVaginal
Dérmicas Insjlacioneseirrigaciones Inhalatorias
Vías de administración
Vías
Oral Sublingual Tópica Parenteral
Vía parenteral
• Intravascular
• Extravascular
- I.M.: Zona bien irrigada, lo que favorece su absorción
Precaución: Lesión de vasos, nervios,…
C.I.: anticoagulados
-S.C.: Absorción más lenta y menor volumen
Se puede emplear en anticoagulados
A favor de las formulaciones LA
• La adherencia al TAR es subóptima en un elevado número de
pacientes, incluso en aquellos con STR.
• Los pacientes están envejeciendo y suelen estar
polimedicados (elevado número de fármacos).
• Disponemos de experiencia previa (ej. IFN convencional vs
PegIFN)
• La carga viral comunitaria podría disminuir si los pacientes
mantienen una adherencia del 100%.
Margolisetal.Lancet2017
LATTE-2: cabotegravir + rilpivirina i.m.
Randomización 2 : 2 : 1
CAB 30 mg QD + ABC/3TC
(N = 309)
Inducción (oral) Mantenimiento (si RNA <50 cop/mL en la semana 4)
CAB 600 mg IM + RPV 900 mg IM /8 sem. (N = 115)
CAB 30 mg QD + ABC/3TC QD (oral) (N = 56)
CAB 400 mg IM + RPV 600 mg IM/4 sem. (N = 115)
Naive > 18 years
HIV RNA >1000 cop/mL CD4 >200/mm3
HBsAg negative ALT <5 UNL
Creatinine cl > 50 mL/min
S48 S96 S32 S-20 D1 S-4
Margolisetal.Lancet2017
LATTE-2: cabotegravir + rilpivirina i.m.
0
10
20
30
40
50
60
70
80
90
100
Éxito Fracaso Sin datos
v.o.
/4 sem
/8 sem
CROI2016
Grobler et al
Copyright © 2017 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.
groblerj_193313-0001-CROI_Poster_v2.00, 2/6/2017 4:47 PM, Size: 93”wx45”h @ 200%, Due WP 2/7
MK-8591 Concentrations at Sites of HIV Transmission and Replication
Jay A. Grobler; Carolyn McHale1; Carol Freddo2; Dan Dreyer2; Li Sun2; Marissa Vavrek2; Sheila Breidinger2; Kerry Fillgrove2; Daria J. Hazuda1; Ming-Tain Lai1 Departments of: 1Infectious Disease (West Point, PA), 2Pharmacokinetics, Pharmacodynamics and Drug Metabolism (West Point, PA), Merck & Co., Inc., Kenilworth, NJ, USA
435
The Level of MK-8591 Anabolites in Monkey Rectal and Vaginal Tissues at 3.9 mpk Dosed at Day 1 and Day 7
Abstract
QWBA Study [14C]MK-8591 in Male Rats at 0.5 Hours After 50 mg/kg P.O. Single Dose
Background: MK-8591 is a long-acting nucleoside reverse transcriptase translocation inhibitor (NRTTI) that has demonstrated potent antiviral activity in HIV-1–infected subjects administered a once-weekly (QW) 10-mg dose as monotherapy in a clinical trial and in SIV-infected rhesus macaque models. MK-8591extended-duration dosing potential was suggested by the long intracellular half-life of MK-8591-triphosphate(MK-8591-TP) in peripheral blood mononuclear cells (PBMCs) in vitro and in preclinical models. Here wedescribe the tissue distribution of MK-8591 and its anabolites in rats by quantitative whole-bodyautoradiography and in rhesus vaginal and rectal mucosa by biopsy.
Methods: Wistar Hannover rats dosed orally at 50 mpk (mg/kg) of [14C]MK-8591 were sacrificed at 0.5 hours and 24 hours, cryosectioned (40 μm thick sagittal), and phosphor imaged after a 4 day exposure. Radioactivity in tissues was quantified using the blood standards along with Raytest AIDA image analysis software. For rectal and vaginal tissue distribution studies, monkeys were dosed 3.9 mpk orally on Days 1 and 8. PBMCs were isolated from blood collected at Days 1, 7, 14, and 21. Colorectal and vaginal biopsies were collected on Days 7 (predose) and 14, pooled separately, and snap-frozen with liquid nitrogen. PBMC and biopsy samples were analyzed by LC-MS/MS.
Results: In rat, MK-8591-related material distributed widely within 30 minutes of dosing and was notably enriched in lymphoid tissue (75.9 nmol-eq/g) compared with blood (lymph node:blood ratio = 2.7). In rat, MK-8591-related material remained enriched in lymphoid tissue at 24 hours (11.1 nmol-eq/g; lymph node:blood ratio = 7.1). In rhesus macaques, on Days 7 and 14, levels of MK-8591-TP in rectal tissue (36 pmol/g and 31 pmol/g) were similar to those measured in vaginal tissue (49 pmol/g and 78 pmol/g).
Conclusions: The levels of MK-8591-TP achieved in both rectal and vaginal tissue are comparable to the levels of tenofovir diphosphate observed in rectal tissue from human subjects treated with tenofovir disoproxil fumarate. Given the significantly greater potency of MK-8591 (IC50 = 0.2 nM) compared with TDF (IC50 = 73 nM), these data suggest utility of MK-8591 for prophylaxis in both men and women. In addition, as lymphoid tissues are sites of active HIV replication and persistence, the observation that MK-8591 is enriched in lymphoid tissues in rats suggests the potential to address the ongoing replication of HIV in lymph nodes.
• The levels of MK-8591-TP achieved in both rectal and vaginal tissueare comparable to the levels of tenofovir diphosphate observed in rectaltissue from human subjects treated with tenofovir disoproxil fumarate
• Given the significantly greater potency of MK-8591 (IC50 = 0.2 nM)compared with TDF (IC50 = 73 nM), these data suggest utility ofMK-8591 for prophylaxis in both men and women
• As lymphoid tissues are sites of active HIV replication and persistence,the observation that MK-8591 is enriched in lymphoid tissues in ratssuggests the potential to address the ongoing replication of HIV inlymph nodes
Conclusions
Reference: Kashuba, ADM., 17th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. June 8-10, 2016, Washington, DC, USA. • May be more appropriate to use LN/PBMC ratios to assess potential accumulation in LN
Dose MK-8591 3.9 mpk QW PO; QW dosing at Day 1 and Day 7
• 3 male + 3 female Rhesus monkeys per drug
• Sample collection for 3 weeks
• Mucosal tissue and secretions at Days 7, 14, and 21
• PBMC samples at Days 1, 7, 8, 14, and 21
• Plasma PK samples collected almost daily
• As opposed to TDF (the TFV-DP level is much lower in vaginal tissues), the level of anabolites invaginal and rectal tissues are comparable for MK-8591
• The level of TP at 3.9 mpk is comparable to the level of TFV-DP in rectal tissue at a dose of 300 mgin humans. Of note, uptake of MK-8591 is more efficient in humans than in monkeys
• The intrinsic EC50 of MK-8591-TP (30 nM) is 10 times more potent than TFV-DP (340 nM) in theantiviral assay with PBMCs
[14C]MK-8591 concentrations in captured lymph nodes
nmol-eq/g
Lymph Nodes 0.5 hr 24 hr
Lymph node – brachial 75.17 12.12
Lymph node – inguinal 73.58 12.71
Lymph node – sciatic 85.63 ND
Lymph node – submandibular 69.04 8.37
LOQ 2.10 1.86
Sciatic lymph node Inguinal lymph node Brachial lymph node Cervical lymph node
Inguinal lymph node Brachial lymph node
Top: Scanned optical image of 40 µm male rat whole-body sagittal sections. Bottom: Autoradiograph of 40 µm male rat whole-body sagittal sections. Dark areas represent presence of radiolabel-related material.
Plasma PK and TP Level in PBMCs
Lymph node:blood ratio
Lymph Nodes 0.5 hr 24 hr
Lymph node – brachial 2.69 7.80
Lymph node – inguinal 2.63 8.18
Lymph node – sciatic 3.06 ND
Lymph node – submandibular 2.47 5.39
From 28-day rat tolerability study
Total intracellular DRM = ~16 µM at t = 2 hours post-dose on Day 28 of 50 mg/kg/day group
MK-8591–associated radioactivity in lymph nodes exceeds blood levels at 0.5 and 24 hours post-dose
The Level of MK-8591 Anabolites in Monkey Rectal and Vaginal Tissues at 3.9 mpk Dosed at Day 1 and Day 7
QWBA Study [14C]MK-8591 in Male Rats at 24 Hours After 50 mg/kg P.O. Single Dose
Day 7 Day 1 Day 14 Day 21
Assuming nmol/g = nmol/mL, the concentration of the anabolites are as follows:
MK-8591 (nmol/g) MK-8591-DP (nmol/g) MK-8591-TP (nmol/g)
Days 7 14 21 7 14 21 7 14 21
Vaginal 0.033 BLQ BLQ 0.095 0.123 BLQ 0.049 0.078 BLQ
Rectal 0.028 0.041 BLQ 0.186 0.168 0.021 0.036 0.031 BLQ
MK-8591 (nM) MK-8591-DP (nM) MK-8591-TP (nM)
Days 7 14 21 7 14 21 7 14 21
Vaginal 33 BLQ BLQ 95 123 BLQ 49 78 BLQ
Rectal 28 41 BLQ 186 168 21 36 31 BLQ
MK-8591 QW PK Study Design
0 3 6 9 1 2 1 5 1 8 2 10 .0 0 0 1
0 .0 0 1
0 .0 1
0 .1
1
1 0
D ru g L e v e ls in R h e s u s P la s m a
T im e (d a y s )
µM
MK
-85
91
n = 6
1 7 8 1 4 2 10
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1 0
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2 0
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T P L e v e ls in R h e s u s P B M C s
T im e (d a y s )
pm
ol/m
illio
n c
ells
n = 6
MK-8591 Enriched in Lymphoid Tissue Compared With Blood
B. Rectal tissue (3 male and 3 female)
A. Vaginal tissue
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T im e (d a y s )
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tis
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n =3
B L Q
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T im e (d a y s )
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n =3
B L Q
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B L Q
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B L Q
Top: Scanned optical image of 40 µm male rat whole-body sagittal sections. Bottom: Autoradiograph of 40 µm male rat whole-body sagittal sections. Dark areas represent presence of radiolabel-related material.
CROI2017
2018
(2018)
En contra de las formulaciones LA
• Temor a las inyecciones.
• Debe definirse “adecuadamente” la periodicidad (¿± días?).
• ¿Volumen de la inyección = inflamación = dolor?
• ¿Cómo manejar la posible toxicidad?
Vías
IntradérmicaSubcutáneaIntramuscularIntravenosa
Vías
OpjcaNasalOcularRectalVaginal
Dérmicas Insjlacioneseirrigaciones Inhalatorias
Vías de administración
Vías
Oral Sublingual Tópica Parenteral
Vía tópica dérmica
• Difusión del fármaco a través de la microcirculación
dérmica
• Ventajas:
- Puede mejorar el cumplimiento
Hametal.TherDeliv2015
Hametal.TherDeliv2015
Vía nasal
Vía rectal
• Absorción más lenta que la gastrointestinal
• Inconvenientes:
- ¿Adherencia?
- ¿Microbiota?
hTp://lab.elmundo.es/inteligencia-arjficial/salud.html
La aplicación de las nuevas tecnologías puede ofrecer soluciones “a medida” para los diferentes problemas a los que nos enfrentamos en la lucha contra el VIH