Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron ... · Farmacocinética e...
Transcript of Servei de Malalties Infeccioses Hospital Universitari Vall d’Hebron ... · Farmacocinética e...
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.