Farmacocinética

e Interaccionese Interacciones

Dr. Esteve Ribera

Servei de Malalties Infeccioses

Hospital Universitari Vall d’Hebron.

Barcelona

Interacciones ARV – ARV

Interacciones ARV – otros fármacos

Farmacocinética/genómica ARV

CROI 2015: Farmacología CROI 2015: Farmacología

Farmacocinética/genómica ARV

Tejidos y reservorios

Embarazo

Pediatría

Interacciones entre ARV:

• BMS-663068 – ETR, DRV/r (523)• BMS-663068 – ETR, DRV/r (523)

A

BMS-663068

600 mg BID

Cohort 1

N=14

B

DRV/r

600 mg/100 mg BID

A + B

BMS-663068 600 mg BID

+ DRV/r 600 mg/100 mg BID

2-day

WO

A

BMS-663068

600 mg BID

Cohort 2

N=14

C

ETR 200 mg BID

A + C

BMS-663068 600 mg BID

+ ETR 200 mg BID

2-day

WO

Days 5-6

600 mg BIDN=14 ETR 200 mg BID+ ETR 200 mg BID

A

BMS-663068

600 mg BID

Cohort 3

N=14

B + C

DRV/r

600 mg/100 mg BID

+ ETR 200 mg BID

A + B + C

BMS-663068 600 mg BID

+ DRV/r 600 mg/100 mg BID

+ ETR 200 mg BID

Days 1–4 Days 7–16 Days 17–26 Day 27

(Discharge)

2-day

WO

Healthy

subjects

• AUC 63%

• Cmax 52%

• Cmin 88%

BMN-663068 600 mg BID

BMN-663068 600 mg BID + DRV/r 600/100 mg BID

BMN-663068 600 mg BID

BMN-663068 600 mg BID + ETR 200 mg BID

• AUC 50%

• Cmax 48%

• Cmin 52%

BMS-626529: substrate of the P-glycoprotein transporter and metabolized by an esterase-mediated

hydrolysis pathway, with contributions from a cytochrome P450 (CYP)3A4-mediated oxidative pathway.

DRV/r + BMS-663068: plasma concentration of BMS-626529:

� Increased exposures were not associated with an increase of AEs.

ETR + BMS-663068: plasma concentration of BMS-626529:

� Decrease in exposure not be expected to affect the efficacy.

• AUC 34%

• Cmax 53%

BMN-663068 600 mg BID

BMN-663068 600 mg BID +

DRV/r 600/100 mg BID + ETR 200 mg BID

DRV/r + ETR + BMS-6265529: Light increase in BMS-6265529.

BMS-663068 + DRV/r + ETR was generally safe in healthy subjects.

BMS-663068 had no relevant effect on the PK of DRV/ ETR .

This drugs may be coadministered without dose adjustment.

• Cmax 53%

• Cmin 33%

Interacciones entre ARV y anti-VHC

• Ledipasvir, Sofosbuvir – ARV (82)

• Grazoprevir, Elbasvir – DTG (522)

Dasabuvir

Beclavuvir

NS5B

polymerase

Inhibitors

Tegobuvir

Flibuvir

Cyclophylin

inhibitorsHCV

TPV, BOC

Simeprevir

Asunaprevir

Paritaprevir

NS3/4

protease

inhibitors

Daclatasvir Omnitasvir

NS5A inhibitorsGSK-2336805 ACH-2928 BMS824393 IDX719

PPI-461 PPI-668 ACH-3102

Flibuvir

Lomibuvir

Setrobuvir

MK-3281 GS-

9669

BI-207127

TMC-647055

+++++

−

protease

inhibitors

Danoprevir

Faldaprevir

Sovaprevir

Vaniprevir

GS-9451

GS-9256

BILN-2061

ACH-2684

ATV/r+TRUN=24 (sanos)

96%

68%

118%

42%

N=24 (sanos)

ATV/r+TRU

63%45%

DRV/r+TRUN=24 (sanos)

N=24 (sanos)

DRV/r+TRU

48%

tenofovir

47% 47% 50%

64%59%

Study treatments were generally well tolerated.

Changes in LDV, SOF or GS-331007 are not clinically significant (LDV/SOF trials)

Increases in ATV or RTV possibly not relevant (other trials)

Patients should be monitored for TFV-associated adverse reactions.

Staggered administration did not mitigate these interactions.

• AUC 19%

• Cmax 36%

• Cmin 14%

• AUC

• Cmax

• Cmin

Grazoprevir 200 mg + Elbasvir 50 mg (n=12)

Grazoprevir 200 mg + Elbasvir 50 mg + Dolutegravir 50 mg (n=12)

Coadministration of DTG with GZR and EBR decreased GZR exposure, but it is in

the therapeutic window.

The PK of EBR when coadministered with GZR is similar with or without DTG.

• AUC

Dolutegravir 50 mg (n=12)

GZR 200 mg + EBR 50 mg +

Dolutegravir 50 mg (n=12)

• AUC

• Cmax 22%

• Cmin

GZR and EBR coadm. has no clinically meaningfull effect on DTG PK.

GZR and EBR can be coadministered in HIV/HCV-coinfected patients receiving

ART with DTG without dose adjustment.

ARV SIME

PREVIR150 mg QD

SOFOS

BUVIR400 mg QD

LEDIP

ASVIR90 mg QD

DACLAT

ASVIR60 mg QD

GRAZO

PREVIR(MK-5172)

100 mg QD

ELB

ASVIR(MK-8742)

50 mg QD

*Abbvie 3D +

150/100/25 mg

QD + 250 mg BID

ATV/r SIM TDF DAC 30 mg GRA ELB ATV (no RTV)

DRV/r SIM TDF GRA ELB DRV (no RTV)

LPV/r SIM TDF GRA ELB PAR; +RTV

EFV SIM DAC 90 mg GRA ELB toxicidad

ETR SIM ND

Antirretrovirales – anti VHC (DDA)

ETR SIM ND

RPV RPV

DTG ND ND ND

EVG/c TDF DAC 30 mg

RAL

MVC

ITIAN

• NS3/4 protease inhibitors: … previr

• NS5A inhibitors: … asvir

• NS5B polymerase inhibitors: … buvir

* ABBVIE 3D+ =

paritaprevir (ABT-450)/ritonavir/

ombitasvir (ABT-267) + dasabuvir (ABT-333)

Interacciones entre ARV y otros fármacos:

• Rifampicina – Doravirina, DRV/r (521,532)

• Atovacuona – EFV, ATV/r (520)

• Malaria – ARV (513)

• Levonorgestrel – EFV (85LB)

• Antidiabéticos – EFV (531)

N=11

N=10

• AUC 88%

• Cmax 57%

• Cmin 97%

Doravirine

• Cmin 97%

• Cmin < 78 nM

Contraindicada la coadminisración de doravirina y rifampicina

Physiologically-based pharmacokinetic (PBPK) modelling represents an innovative

approach to simulate clinical scenarios in the absence of clinical data.

The PBPK modelling is a bottom up technique which aims to simulate PK combining

system data (e.g. demographics, physiology, anatomy and genetics) describing a

population of interest and in vitro drug data (e.g. Caco-2 permeability, protein binding,

intrinsic clearance, lipophilicity) through a mathematical description of absorption,

distribution, metabolism and elimination (ADME) processes

• AUC 58%

• Cmax 35%

• Cmin 79%

DRV/r 800/100 QD

alone / with RIF

• AUC 11%

DRV/r 800/100 QD alone vs.

RIF + DRV/r 1600/200 QD

The developed PBPK model predicted the in vivo PK of DRV/r and the interaction with RIF.

DRV/r 1600/200 mg QD or 800/100 mg BID could mitigate the effect of RIF on DRV/r PK.

These findings are in agreement with a recently published population pharmacokinetic

approach where 800/100 mg and 1200/150 mg both bid and 1600/200 mg qd could

largely overcome the impact of the interaction.

• AUC 11%

• AUC 18%

DRV/r 800/100 QD alone vs.

RIF + DRV/r 800/100 BID

Atovaquone is an alternative agent for prophylaxis and treatment of PCP and toxoplasmosis.

Cavg ≥14 μg/mL and ≥18.5 μg/mL are predictive of successful treatment of PCP and toxoplasmosis.

N=30 HIV+: 10 EFV, 10 ATV/r, 10 no ART. Steady state. Random ATOV 750/12h, wash out, 1500 mg/12h

EFV + atovaquone is associated with reduced (~50%) atovaquone plasma concentrations.

With ATV/r PK values did not differ significantly from control group values.

750:Cavg < 14 μg/mL in 4/10 subjects taking EFV: higher atovaquone doses are necessary.

With atovaquone 1500 mg BID, concentrations are adequate (Cavg > 18.5 μg/mL)

• AUC 47%

• Cavg 47%

• AUC 44%

• Cavg 44%

PK-PD in HIV infected children on ART or controls (HIV-uninfected children).

Treatment for malaria: Artemether-Lumefantrine (AR-LR)

Based treatment for HIV: LPV/r (n=30); EFV (n=31); NVP (n=30) and control (n=51)

Dihidroartemisinin (DHA)Artemether (AR)

• EFV 56%

• NVP 64%

• LPV/r

AUC: • EFV 68%

• NVP 29% (NS)

• LPV/r

AUC:

• EFV 50%

• NVP

• LPV/r 108%

LR AUC

28-day parasitologic failure:

Dramatic alterations in antimalarial drug exposures in the setting of concomitant ART.

Results support the need for alterantive dosing of artemether-lumefantrine in the

setting of EFV or viceversa.

Lumefantrine (LR)

28-day parasitologic failure:

EFV 38% (HR 3.0) (p=0.01)

NVP 30% (HR 2.3) (p=0.06)

LPV/r 13% (ref)

42-day recurrent malaria:

EFV 25% (HR 2.3)

NVP 24% (HR 2.7)

LPV/r 11% (ref)

LEVONORGESTREL

SUBDERMAL IMPLANT

CONTRO GROUP (n=17)

EFAVIRENZ GROUP (n=20)

Lev

on

org

est

rel

con

cen

tra

tio

n (

pg

/mL)

Levonorgestrel concentrations reduced by 45-57%.

3 pregnancies observed in the EFV group (15%); none in the Control group.

Other effective contraception options for women on EFV-based ART

0 10 20 30 40 50

Lev

on

org

est

rel

con

cen

tra

tio

n (

pg

/mL)

Weeks

Pioglitazone and Repaglinide are metabolized by CYP2C8 (EFV inhibitor) and CYP3A4 (EFV inducer)

AUC 41%, Cmax 25%

PIO 15 vs PIO 22,5 + EFV

AUC = , Cmax 12%REP 2 vs REP 5+EFV

AUC y Cmax =

PIO 15 vs PIO 15 + EFV

AUC 64%, Cmax 60%

REP 2 vs REP 2 + EFV

EFV reduced PIO exposure but increase in PIO dosage from 15 to 22.5 mg QD was able to

compensate for EFV induction.

EFV reduced REP exposure but increase in REP dosage from 2 to 5 mg TID was able to

compensate for EFV induction.

AUC y Cmax =

Farmacocinética ARV

Farmacogenómica

• IR TDF – LPV/r, NNRTI (511,792)• IR TDF – LPV/r, NNRTI (511,792)

• UGT1A1 – ATV/r (515)

1.0

0.8

0.6

0.4

0.2

TDF 300 mg q48 (Creat cl. 30-49 ml/min)

Ten

ofo

vir

co

nce

ntr

ati

on

(μ

g/m

L)

LPV/r (n=18 HIV+)

NNRTI (n=19 HIV+)

• AUC 67%

• Cmax 55%

• Cmin 75% P = 0.50

1000

800

600

400

Ten

ofo

vir

–D

F c

on

c (f

mo

l/1

06

cell

s)

0.2

00 6 12 24 36

48Time (hours)

Ten

ofo

vir

co

nce

ntr

ati

on

q48h

LPV/r

q48h

NNRTI

200

0

Cla

stTe

no

fov

ir

Significantly higher tenofovir exposure among patients with moderate renal

dysfunction receiving LPV/r compared to NNRTI.

This increase of TFV AUC and Cmax was 2-fold higher than those previously

reported with normal renal function.

No difference in TFV-DF was found

ACTG-5257

In A5257, UGT1A1 T/T

genotype increased

likelihood of bilirubin-

associated ATV/r

discontinuation.

Likelihood of bilirubin-

associated ATV/r

discontinuation was discontinuation was

least in Black,

intermediate in

Hispanic, and greatest in

White participants. We

speculate that

differential rates of

discontinuation may

reflect differences in

physical manifestations

of icterus by

race/ethnicity.

ACTG-5257

� Among A5257 participants

with non-T/T UGT1A1 geno-

types, tolerability failure in

ATV/r was almost within the

equivalence boundary com-

pared to DRV/r but was < RAL.

� Knowledge of UGT1A1 geno-

type would allow ATV/r to be

prescribed to the substantial prescribed to the substantial

subset of individuals at low risk

for bilirubin-related ATV/r

discontinuation.

In settings where drug costs

encourage prescribing of ATV/r

regimens, patient care may

benefit from screening for

UGT1A1 geno-typing, with

avoidance of ATV/r in the select

subset of patients at greatest

risk for bilirubin-related

discontinuation.

Concentración de ARV en tejidos y reservorios:

• Tejido testicular (534)

• PK TAR preventivo

• Imagen distribución espacial

• Acceso a reservorios con nano formulaciones varias

Drug [Plasma]

(ng/mL)

[Testes]

(ng/mL)

DRV

RTV

2044

49

397

389

TFV

FTC

62

214

45

252TFV and FTC shows similar concentrations in plasma

and testicular tissue. 3TC varies from patient to

patient.

3TC

EFV

208

7449

147

1856

3TC

DRV

RTV

126

2376

236

140

523

683

TFV

3TC

ATV

RTV

51

137

1300

272

44

24

1030

524

Major drug transporters and drug metabolic

enzymes relevant to ART can be found in testicular

tissue.

Overall, teste are a complex pharmacological

compartment that needs more studies.

patient.

RTV shows higher tissue concentrations. DRV and

ATV shows lower tissue concentrations.

These data align with drug transporter and drug

metabolic enzyme expression patterns.

PK – embarazo y lactancia:

• Raltegravir (891)

• Etravirina (892-893)• Etravirina (892-893)

• Rilpivirina (894)

• ARV en cabello (887)

450

400

350

300

250

200

150

RA

L C

12

h(n

g/m

L)

150

100

50

0

RA

L C

RAL concentrations were not significantly modified during pregnancy and are similar to

historical data in non pregnant population.

All patients except one late presenter reached VL < 400 c/mL. No neonate HIV infected.

RAL containing regimens were effective and safe for mothers and children.

Favourable placental transfer (RCB/MP>1.0) and in amniotic fluid (RAF/CB =1.05)

AUC

C

Unlike other cytochrome CYP3A4 substrates, etravirine exposure trends towards

being higher in the 3rd trimester compared to postpartum (2nd trimester and

postpartum exposure are similar to non-pregnant historical controls)

Etravirine transplacental passage is high.

Ctrough

Cord Blood/Maternal Plasma Ratio: 0.76 (0.19 – 4.25)

N=5 N=13 N=9

1200

1000

800

600

Pla

sma

co

nce

ntr

ati

on

of

ET

R(n

g/m

L)

Second trimester (n = 13) Third trimester (n = 10) Postpartum (n = 10)

• AUC 28%

• Cmax 31%

• Cmin 93%

• AUC 46%

• Cmax 39%

• Cmin 131%

ETR exposure increased during pregnancy. The regimen was well tolerated.

Virologic response was maintained, without mother-to-child transmission.

These data indicate ETR 200 mg bid could be a treatment option for HIV-1

infected pregnant women.

400

200

0

Pla

sma

co

nce

ntr

ati

on

of

ET

R

Time (h)0 1 2 3 4 6 9 12

160

140

120

100

80

Ril

piv

irin

e

con

cen

tra

tio

ns

(ng

/mL)

Second trimester Third trimester

Postpartum Non-Pregnant

N=26

No significant differences in RPV exposure during pregnancy and postpartum.

The standard RPV dose provides adequate RPV exposure during pregnancy.

60

40

20

0

Me

din

Ril

piv

irin

e

con

cen

tra

tio

ns

(ng

/mL)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time After Dose (h)

Hair concentrations of EFV and LPV predicted viral

suppression at delivery and 24 w postpartum.

ARV hair conc. were more strongly associated with

viral suppression than selfreported Adherence.

Hair conc. of ARVs could serve as innovative tool to

explain virologic outcomes in research studies.

Defining thresholds for ARV hair concentrations

associated with failure in larger cohorts.

PK – pediatría:

• Elvitegravir + IP/r (951)

• EVG/cobi/FTC/TAF (953)

All subjects (n=14) (6 – 12 yr) EVG + IP/r +

17 to < 30 kg (n=8) (EVG 50 mg)

≥ 30 kg (n=6) (EVG 85 mg)

Administration of EVG once daily with a PI/r in children 6 to <12 years old

provides therapeutic EVG exposure, mean trough concentrations ~11-fold

above the protein-binding adjusted IC95 (44.5 ng/mL)

Historical controls

TAF TFV

HIV-infected treatment-naïve adolescents (12-18 years), n = 50

EVG/Cobi/FTC/TAF FDC

TAF and TFV exposures in adolescents are consistent with exposures in adults

TFV exposures are ~90% lower than TFV exposures from TDF

E/C/F/TAF is well-tolerated through Week 24

E/C/F/TAF exhibits high antiviral activity (all VL<50c/mL)

DRV/r con o sin ETR y ETR sin IP [BMS-626529]. No es

necesario ajuste de dosis.

Ledipasvir/Sofosbuvir – ATV/r o LPV/r + TDF/FTC:

� Algunas interacciones significativas pero sin relevancia clínica

( 47-59% [TFV]: monitorización).

2015 PK: Resumen y Conclusiones 12015 PK: Resumen y Conclusiones 1

Grazoprevir/Elbasvir – Dolutegravir: No interacciones PK

Rifampicina [Doravirina]: Asociación contraindicada.

Rifampicina [DRV/r]: � dosis 1600/200 QD o 800/100 BID ?

EFV [Atovacuona]: Doble dosis (1500 mg/12h).

ATV/r – Atovacuona: No interacciones PK.

Artemether/Lumefantrina – ITIAN, IP/r:

� EFV [AR, DHA, LR]: Menor eficacia (no coadministrar)

� NVP [AR]: Evitar? según opciones.

� LPV/r [LR]: Dosis estándar.

EFV [Levonorgestrel] y eficacia: No coadministrar.

2015 PK: Resumen y Conclusiones 22015 PK: Resumen y Conclusiones 2

EFV [Levonorgestrel] y eficacia: No coadministrar.

EFV [Pioglitazona] y [Repaglinide]: � dosis.

Insuf. renal moderada: Mayor [TFV] con IP/r vs ITIAN.

Interrupción ATV/r en ACTG5227: UGT1A1 genotipo T/T.

Testículos: compartimento farmacológico complejo con

concentraciones variables de ARV.

Embarazo:

� [Raltegravir]: No se modifica. Cruza bien la barrera

placentaria. Bien tolerado y eficaz.

� [Etravirina]: . Cruza bien la barrera placentaria. Bien

tolerado y eficaz.

� [Rilpivirina]: No se modifica. Bien tolerado y eficaz.

2015 PK: Resumen y Conclusiones 32015 PK: Resumen y Conclusiones 3

� [Rilpivirina]: No se modifica. Bien tolerado y eficaz.

Pediatría:

� Elvitegravir + IP/r (6-12 años): [EVG] terapèuticas con dosis de

50 mg (peso < 30 kg) u 85 mg (peso >30 kg).

� EVG/cobi/FTC/TAF (12-18 años): [TAF] y [TFV] similares a las

de adultos. Bien tolerado y eficaz.