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 )

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91

n = 6

1 7 8 1 4 2 10

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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

7 1 4 2 10 .0 0 1

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7 1 4 2 10 .0 0 1

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n =3

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7 1 4 2 10 .0 0 1

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7 1 4 2 10 .0 0 1

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tis

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mo

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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