What is the pharmacological support

for reduced drug regimens?

Esteban Ribera MD, PhDServei de Malalties Infeccioses

Hospital Universitari Vall d’HebronBarcelona

What is the PK support for reduced drug regimens?

PK-PD: robustez farmacológica.

Factores relacionados con el éxito terapéutico.

Interacciones farmacocinéticas.

Bases PK de 2DR long acting.

Concentraciones en santuarios.

Exposición a fármacos a largo plazo.

Combinaciones 2DR en EC o cohortes (naive o switch)

IDV + EFV

LPV/r + EFV

LPV/r + RAL

ATV + RAL

DRV/r + RAL

ATV/r + MVC

DRV/r + MVC

LPV/r + 3TC

ATV/r + 3TC

DRV/r + 3TC

DRV/r + ETR

DRV/c + RPV

DTG + 3TC

DTG + RPV

CAB LA + RPV LA

DTG + DRV/c

ToxicidadEficacia (<CV basal elevada)Resistencias

DRV/c + 3TC

Combinaciones 2DR en ensayos clínicos / cohortes

ITIAN3TC

IP/pDRV/c

ITINNRPV

INIDTG

CAB

Core

Potencia

Barrera genética / robustez

Robustez farmacológica

PK-PD. Cociente inhibitorio. Robustez farmacológica

ARV * PA-EC50/90

(ng/mL)

Cmin

(ng/mL)IQ

Darunavir/p 50 1500 ≈ 30

Dolutegravir 64 1200 ≈ 20

Cabotegravir 160 4700 ≈ 30

Raltegravir 15 70 ≈ 5

Etravirina 60 300 ≈ 5

Rilpivirina 12 70 ≈ 6

* Dosis oral: DRV/r 800/100 mg QD; DTG 50 mg QD; CABO 30

mg QD; RAL 400 mg BID; ETR 200 mg BID; RPV 25 mg QD.

PA-EC: Concentración efectiva ajusta por unión a proteínas

www.hiv-druginteractions.org; Moltó J. Virology Education, Málaga, 2017

Cociente inhibitorio = Concentración plasmática / Actividad intrínseca

Robustez farmacológica

IQ = Cmin / PA-EC

DRV/c

DTG CAB

3TC RAL

RPV ETR

core

2DR: 1 core + 1 acompañante

Combinaciones 2DR en EC o cohortes

Core(Potencia, barrera genética,

robustez resistencias,

robustez farmacológica)

DTG

CAB

DRV/c

Acompañante

con éxito

3TC

RPV

Acompañante

sin éxito

RAL

MVC

+

Inhibición de la

Transcriptasa

Inversa

NO Inhibición de la

Transcriptasa

Inversa

. Factores éxito

⧓150

50

40

30

20

10

0

T 1/2

(ho

ras)

ZDV

d4

T

AB

C

3TC

dd

I

TDF

FTC

NV

P

EFV

ETR

RP

V

NFV

SQV

/r

FPV

/r

LPV

/r

ATV

/r

TPV

/r

DR

V/r

EVG

/c

RA

L

MV

C

DTG

ITIAN ITINN IP ICCR5 INSTI

12 h

24 h

Intracelular Plasma

¿Importancia de la vida media de los ARV?

Adaptado de: Arribas JR. IAS, Paris. 2017

T1/2 < 12 horas

CA

B

T1/2 > 12 horas

*

* Larga vida media de disociación del complejo ADN-integrasa (71h)

0 24 483612

Tiempo (horas)

Co

nce

ntr

ació

n d

el f

árm

aco

MEC

Dosis Olvido

dosis

Efecto perdón. PK de ARV con vidas medias diferentes

MEC (concentración mínima eficaz)

MEC

Zona de potencial replicación del VIH en monoterapia (FV, blips, CV>100K, resistencias)

ARV A ARV B

DTG & EVG plasma concentrations up to 216 hours post-dose

Adapted from Elliot E, et al. J Antimicrob Chemother 2015;71:1031–6

*Geometric mean†Therapeutic target concentration

1

10

100

1000

10000

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200 208 216

DTG

EVG

COBI

Time (h)

Pla

sm

a c

on

ce

ntr

ati

on

* (n

g/m

L)

RPV

Regímenes 2DR: Drug-drug interactions

Lamivudina – Dolutegravir o IP/p

Dolutegravir – Rilpivirina y otros NNRTIs

Darunavir/rtv o cobi – Rilpivirina o Etravirina

Dolutegravir – Darunavir/rtv o cobi

Cabotegravir – Rilpivirina

Co

nce

ntr

ació

n d

el A

RV

Tiempo

Elevado margen terapéutico

Toxicidad

Toxicidad

Eficacia

Eficacia

Margen

terapé

utico

100% (x2) irrelevante

50% (:2) irrelevante

Estrecho margen terapéutico

Regímenes 2DR: Drug-drug interactions

Con los actuales fármacos se ha producido un notable cambio en la importancia clínica de

interacciones PK estadísticamente significativas

DTG + 3TC o IP/p + 3TC: Drug-drug interactions

Eliminación

renal sin

metabolizar

(95%)

No inhibidor

ni inductor

de sistemas

metabólicos

Lamivudina (3TC)

No interacción

con otros ARV

DTG ± ITINN: Drug-drug interactions

Dolutegravir (DTG)

Metabolismo:

UGT1A++,

CYP3A (15%)

Transporte:

P-gp, BCRP

Inhibidor de:

OCT2 (1,93 µM)

Inductor de:

No inductor

Efavirenz (EFV)

Metabolismo:

CYP3A4, 2B6

Transporte:

?

Inhibidor de:

CYP2C9, 2C19, 3A4

Inductor de:

CYP3A4, 2B6,2C9,

2C19, UGT1A1

Etravirina (ETR)

Metabolismo:

CYP3A,2C9,2C19

Transporte:

?

Inhibidor de:

2C9,2C19

Inductor de:

CYP3A4,

UGT1A

Rilpivirina (RPV)

Metabolismo:

CYP3A++, 2C19

Transporte:

No

Inhibidor de:

OCT2

Inductor de:

No

1. Song I, et al. IWCP 2011. Abstract 002; 2. Song I, et al. Antimicrob Agents Chemother 2011;55:3517–21; 3. Tivicay US Prescribing Information. June 2016

DTG 50 mg QD + EFAVIRENZ 600 mg QD 1

DTG

co

nce

ntr

atio

n (

µg/

mL)

Post-dose time (hours)

AUC ↓ 57%Cmax ↓ 39%C24 ↓ 75%

La dosis recomendada de DTG si se administra concomitantemente con EFV es de 50 mg/12h

DTG ± EFV or ETR in healthy subjects: drug-drug Interaction

Post-dose time (hours)

DTG

co

nce

ntr

atio

n (

µg/

mL)

DTG 50 mg QD + ETRAVIRINA 200 mg BID 2

AUC ↓ 71%Cmax ↓ 52%C24 ↓ 88%

o ETR es de 50 mg/12h

Interaction between DTG and RPV in healthy subjects

Ford SL, et al. Antimicrob Agents Chemother 2013;57:5472–7.

RPV had minimal effects on DTG PK: no dose adjustment required

DTG had minimal effects on RPV PK: no dose adjustment required

(ng

/mL

)

Inhibición e inducción enzimática. Tiempos de inicio y final

CYP-S

CYP-I

CYP

Inhibición enzimática (competitiva)

Inicio rápido (horas) y recuperación

rápida al suspender el inhibidor

Inductor

RXR PXR

Transcripción

Traslación

Síntesis proteica

(CYP3A4) (UGT1A1)

Inducción

enzimática

DNA

RNA

Inicio gradual: días a semanas (máxima ≈ 9-12 d)

Recuperación gradual tras suspender el inductor (semanas)

3DR: Switch desde EFV a DTG o a RPV

Adkison K. IWCP 2017 # Oral 10; Song I. Eur J Clin Pharmacol 2014;70:1173–9; de Wet J. IWCP 2016 # O23; Crauwels H. Antiviral Ther 2012;17:439–46; Mills A. HIV Clin Trials 2013;14:216–23

Time post-switch

Estudio STRIIVING: Subgrupo de cambio de

EFV + 2 NRTIs a DTG/ABC/3TC

[DTG] > PA-IC90 en todas las muestras tras el cambio.

Eficacia independiente del TAR previo (NN, IP o INI)

No es preciso ajustar la dosis de DTG tras EFV.

Cambio de EFV/FTC/TDF a RPV/FTC/TDF

[RPV] baja 1as sem. A las 4 sem. ya similar a las de referencia.

Las primeras semanas tras stop, [EFV] >> PA-EC90

No es preciso ajustar la dosis de RPV tras el cambio de EFV.

SWORD (DTG + RPV) PK Analysis

Visit

Pre-dose conc, geometric mean (95% CI)

n DTG (µg/mL) n RPV (ng/mL)

Week 4 306 1.26 (1.17, 1.36) 305 71.8 (67.6, 76.3)

Week 24 417 1.36 (1.28, 1.45) 417 79.8 (76.3, 83.6)

Week 48 430 1.34 (1.26, 1.43) 426 82.9 (79.1, 86.9)

All patients who switched to 2DR C0 at Week 4 to 48

comparable to previously observed for DTG and RPV:

DTG C0=1.11 (46) µg/mL (geometric mean; CV, %)2

RPV C0=79 ± 35 ng/mL (mean ± SD; N=679)3

Pooled study resultsNNRTI subset with extra sampling

*Data presented as geometric mean and 95% CI

NNRTI subset: DTG and RPV C0 increased between W 2 and 4, and by

W 4 were comparable to those of the overall SWORD study population

and to previously observed steady-state trough concentrations.

DTG and RPV C0 were above their respective PA-IC90 values, as was

expected based on PK results from prior EFV- and NVP-switch studies.

The efficacy and virology results demonstrate that the DTG and RPV

exposures were sufficient to maintain virologic suppression.

Adkison K, et al. IWCP 2017, # Oral 10

Bioequivalencia DTG/RPV STR vs DTG + RPV

Mehta R, et al. IWCP 2017. Poster 25

DT

G c

on

ce

ntr

ati

on

, µ

g/m

L

0

3.0

3.5

2.0

2.5

1.0

1.5

0

0.5

20 40 60 80 100 120

Time, hours

Dolutegravir

A: FDC DTG/RPV 50 mg/25 mg

B: DTG 50 mg plus RPV 25 mg

RP

V c

on

ce

ntr

ati

on

, µ

g/m

L

0

10

1

0.1

0.01

20 40 60 80 100 120

Time, hours

Rilpivirine

A: FDC DTG/RPV 50 mg/25 mg

B: DTG 50 mg plus RPV 25 mg

N = 113

The DTG/RPV FDC tablet is bioequivalent to co-administration of the DTG 50 mg and RPV 25 mg tablets

under fed conditions and was found to be well tolerated

The FDC of DTG/RPV 50 mg/25 mg was found to be well tolerated with no new safety signals and aligns

with what has been previously observed for both DTG and RPV (SWORD)

DRV/cobi vs rtv + ETR: Drug-drug interactions

DRV + ritonavir

Metabolismo:

CYP3A,2D6

Transporte:

P-gp, MRP1

Inhibidor de: CYP3A>2D6>2C9/19>

>2A6>2E1,P-gp,BCRP, OATPs, MATE‐1

Inductor de:UGT++,CYP1A2,

2B6,2C8,2C9/19

DRV/cobicistat

Metabolismo:

CYP3A4,2D6

Transporte:

OCT2

Inhibidor de: CYP3A, 2D6,P-gp,

BCRP, OATP1B1/

1B3, MATE‐1

Inductor de:

No inductor

Etravirina (ETR)

Metabolismo:

CYP3A,2C9,2C19

Transporte:

?

Inhibidor de:

2C9,2C19

Inductor de:

CYP3A4, UGT1A

Rilpivirina (RPV)

Metabolismo:

CYP3A++, 2C19

Transporte:

No

Inhibidor de:

OCT2

Inductor de:

No

¿Podemos cambiar DRV+RTV+ETR por DRV/c+ETR? ¿Interacciones DRVp con RPV?

Etravirine and darunavir/cobicistat drug-drug Interactions

AUC ∼Cmax ∼C24 ↓ 56%

AUC ∼Cmax ∼C24 ∼

Etravirine were unchanged, but there was a significant decrease in cobicistat exposure and DRV Ctrough

Boosting darunavir with ritonavir instead of with cobicistat may be preferred when combined with etravirine

Moltó J, et al. J Antimicrob Chemother. 2017 Dec 11. doi: 10.1093/jac/dkx459

↓ [cobi]

Rilpivirine and darunavir/cobicistat drug-drug Interactions

Jackson A, et al. HIV Clin Trials 2018;19:31-37

RPV exposure was approximately 45% higher than that determined in ECHO and THRIVE

DRV exposure was comparable with historic data in patients (ARTEMIS, ODIN)

Good tolerability. No QTcF interval changes were recorded

Naive (n=36). DRV 800 mg + RTV 100 mg + RPV 25 mg QD (breakfast 534 kcal)

DRV

RPV

AUC 82.598 ng.h/mL

Cmax 8.381 ng/mL

CƬ 1.728 ng/mL

AUC 3.036 ng.h/mL

Cmax 188 ng/mL

CƬ 116 ng/mL

Ficha técnica RPV (+DRV/r)

AUC RPV ↑130%

Cmax RPV ↑ 79%

Cmin RPV ↑178%No es preciso ajuste de dosis

DTG ± DRV/p: Drug-drug interactions

DRV/ritonavir

Metabolismo:

CYP3A,2D6

Transporte:

P-gp, MRP1

Inhibidor de: CYP3A4>2D6>2C9/19

>>2A6>2E1,P-gp,BCRP, OATPs, MATE‐1

Inductor de:UGT++,CYP1A2,

2B6,2C8,2C9/19

DRV/cobicistat

Metabolismo:

CYP3A4,2D6

Transporte:

OCT2

Inhibidor de:

CYP3A, 2D6,P-gp,

BCRP, OATP1B1/

1B3, MATE‐1

Inductor de:

No inductor

Dolutegravir (DTG)

Metabolismo:

UGT1A++,

CYP3A (15%)

Transporte:

P-gp, BCRP

Inhibidor de:

OCT2 (1,93 µM)

Inductor de:

No inductor

Cohortes + 2 Ensayos clínicos aleatorizados en marcha: DUALIS y D2EFT

DTG ± DRV/r in healthy subjects: drug-drug interactions

1. Adapted from Song I, et al. J Clin Pharmacol 2011;51:237–42; 2. Tivicay US Prescribing Information. June 2016

DTG alone

DTG + DRV/r

AUC ↓ 22%Cmax ↓ 11%C24 ↓ 38%

Post-dose time (hours)

DTG

co

nce

ntr

atio

n (

µg

/mL)

RTV potent inhibitor of

CYP3A4, inducer of UGT1A1

and inhibitor of P-gp.

Two-period, two-sequence,

crossover study of healthy

subjects (15 per group).

DTG 30 mg QD + DRV/r

600/100 mg BID

The magnitude of the

effect is not expected to

be of clinical relevance

Conc. plasmáticas de DRV y DTG (rtv vs cobi)

2033 ± 976 1979 ± 940 599 ± 317 1149 ± 605

Ctrough

Gervasoni C, et al. J Antimicrob Chemother 2017 Jun 1;72(6):1842-1844. doi: 10.1093/jac/dkx055

The switch from ritonavir to

cobicistat resulted in a

comparable boosting effect

on darunavir exposure.

Cobicistat significantly

increased dolutegravir

concentrations.

Co-administration of

dolutegravir and cobicistat

has not shown effect on

serum creatinine.

DTG + DRV/rito DTG + DRV/cobi

PK PKN = 12

Margolis et al. Lancet Infect Dis. 2015;15:1145-1155. Margolis et al. AIDS 2016 Durban #THAB0206LB

Cabotegravir (CAB): Integrase Inhibitor

— Oral 30 mg tablet (t1/2 ∼ 40 hours)

— IM LA injection 200 mg/mL (t1/2 ∼20-40 days)

— Metabolised by UGT1A1 (minor UGT1A9)

— Substrate of P-gp and BCRP

— Low risk of DDI as perpetrator

Rilpivirine (RPV): NNRTI

— Oral 25 mg tablet (t1/2 ∼ 50 hours)

— IM LA injection 300 mg/mL (t1/2 ∼30-90 days)

Base farmacológica para la terapia dual IM (CAB LA + RPV LA)

Interaction between CAB and RPV in healthy subjects

Ford SL, et al. ICAAC 2012, # A-1249; Antimicrob Agents Chemother 2013;57:5472–77.

GSK1265744 = Cabotegravir

No clinically significand DDI between DTG or CAB and RPV.

These support coadministration of RPV with DTG or CAB as either oral or long-acting depot injection regimens.

LATTE-2: Concentraciones plasmáticas de Cabotegravir y Rilpivirina

Margolis et al. CROI 2016; Boston, MA, # 31LB; AIDS 2016; Durban, # THAB0206LB.Cτ, Ctrough; PA-IC90, protein binding–adjusted 90% inhibitory concentration

Both Q4W and Q8W steady state exposures approximate once-daily oral dosing.

(CAB 400 mg IM + RPV 600 mg IM)

(CAB 600 mg IM + RPV 900 mg IM)

(CAB 400 mg IM + RPV 600 mg IM)

(CAB 600 mg IM + RPV 900 mg IM)

0.16 µg/mL 12 ng/mL

CAB loading dose 800 mg

ARVUnión a

proteínas

LCR/

plasma

Semen/

plasma

Recto/

plasma

Vagina/

plasma

Dolutegravir >98.9% 0.05 0.07 0.2 0.1

Cabotegravir >99% 0.08 0.2

Darunavir/p 95% 0.005 0.2 2.7 1.5

Raltegravir 83% 0.03 3.25 231 0.6

Rilpivirina 99.7% 0.02 0.1 1.5-2.5 0.65

Lamivudina <36% 0.12 9.1 67 (FTC) 1.5

Penetración en compartimentos

Distribution and Antiviral Activity in CSF of Dolutegravir

Letendre S, et al. CROI 2013 # 178LB

Pacientes naive que inician DTG + ABC/3TC

Therapeutic [DTG] in CSF for all subjects (> 0.2 ng/mL: in vitro IC50)

[DTG] in CSF were similar to unbound DTG concentrations in plasma.

DTG + ABC/3TC was effective in decreasing CSF HIV-1 RNA (similar to those in plasma)

-3.42 -3.04

(µg/mL)

HIV-1-RNA Decay and Dolutegravir Concentrations in Semen

Blood Plasma (ng/mL) Seminal Plasma (ng/mL) Seminal/Blood ratio (%)

Week 4 Week 24 DTG Free (%) Week 4 Week 24 DTG Free (%) Week 4 Week 24

Median

(range)

1200

(124-2290)

1420

(353-3100)

0.45

(0.39-0.56)

92.2

(15.7-331)

129

(38.8-423)

48

(34.2-59.7)

7.6

(2.8-23.8)

8.7

(4.5-21.9)

HIV-1 RNA Decay Dynamics in BP and SP

Sample HIV-1 RNA <40 c/mL W24

Blood P 13/15 (86.7%)

Semen P 14/15 (93.3%)

Imaz A, et al. EACS 2015 #PS9/5

15 pacientes naive que inicial DTG + ABC/3TC

Total [DTG] in SP is 7.8% of in BP.

DTG unbound fraction in SP is 48%, which allows to

predict free [DTG] in SP several times > than EC50.

Rapid HIV-1 RNA suppression in seminal fluid is

achieved in most patients initiating DTG/ABC/3TC.

DTG concentrations in SP are sufficient to contribute

to a high and rapid antiviral activity in this

compartment

Gathe J, et al. EACS 2017, Milan. # PE9/7; Doe J, et al. EACS 2017, Milan. # PE2/16; Ma Q. EACS 2017, Milano, Italy. PE10/2.

N=12

Darunavir

CSF

Plasma

PREZENT: DRV and RPV Concentrations in Plasma and CSF

12 pacientes naive que inician DRV/cobi + RPV

Rilpivirina

CSF

Plasma

All subjects achieved und VL at CSF (<10 c/mL),

Therapeutic concentrations (>DRV and RPV IC90 at CSF), and

Significant NC improvement.

**

Régimen TAR mg/día g/año

RAL+TDF/FTC

DRV/c/FTC/TAF

DTG/ABC/3TC

EVG/c/FTC/TAF

RPV/FTC/TAF

1300

1160

950

510

250

475,3

423,4

346,8

186,2

91,3

DTG + 3TC

DTG + RPV

350

75

127,8

27,4

CAB + RPV IM600+900 mg Q8W - 9,8

Trip

le t

era

pia

2D

R

Adaptado de: Back D. Virology Education 2017. http://regist2.virology-education.com/2017/2GlobalHCF/05_Back.pdf (acceso noviembre 2017)

LA

1,37kg

17,34kg

50 años de TAR

0,49 kg

Cantidades de fármaco recibidas según el régimen de TAR

Adaptado en parte de: Back D. Virology Education 2017 Marcotullio S et al. EACS 2017 Milan, #PE25/9

What is the PK support for reduced drug regimens? Summary

Importancia de los aspectos farmacológicos.

Al menos un fármaco robusto (core con IQ elevado)

El 2º ARV con vida media prolongada (> 12 h, similar a core)

No interacciones PK clínicamente significativas entre ambos.

Buena penetración en compartimentos.

Reducir la exposición a fármacos a largo plazo.