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FARMACOLOGIA CLINICA DELLA TERAPIA ANTIRETROVIRALE. Giovanni Di Perri CLINICA DI MALATTIE INFETTIVE Università degli Studi di Torino. Ospedale Amedeo di Savoia. Antiretroviral Drug Approval: 1987-2009. NRTI, Nucleoside reverse transcriptase inhibitor; - PowerPoint PPT Presentation
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Ospedale Amedeo di Savoia
Giovanni Di Perri
CLINICA DI MALATTIE INFETTIVE
Università degli Studi di Torino
FARMACOLOGIA CLINICA DELLA TERAPIA ANTIRETROVIRALE
Antiretroviral Drug Approval: 1987-2009
MaravirocRaltegravirEtravirine
Darunavir
Tipranavir
EnfuvirtideAtazanavirEmtricitabineFosamprenavir
Tenofovir
Lopinavir/r
Amprenavir
EfavirenzAbacavir
NelfinavirDelavirdine
RitonavirIndinavirNevirapine
3TCSaquinavir
d4TddCddl
AZT
• NRTI, Nucleoside reverse transcriptase inhibitor;• NNRTI, Non-nucleoside reverse transcriptase inhibitor;• PI, protease inhibitor• Integrase Inhibitor• CCR5 Antagonist/Entry Inhibitor
HIV CYCLEHIV CYCLE
BINDING
UNCOATING
REVERSETRANSCRIPTION
INTEGRATION
TRANSCRIPTION
TRANSLATION
ASSEMBLY
PROTEASE
genomic RNA
double strandedDNA
genomic RNA
viral proteins
cellmembrane
cell nucleus
proviral RNA
viral mRNA
ProteaseInhibitors
BUDDING
CD4
CCR5 CXCR4
RT InhibitorsN/tRTIsNNRTIs
Fusion inhibitors
co-receptors inhibitors
integrase inhibitors
mwg/mol
OralBioav.
%
VD Protein binding
%
Plasma T/2h
IC PPP T/2
h
Elimination(major route)
AZT 267.24 64 1.6 + 0.6 L/Kg
< 25 0.5 - 3 7
d4T 224.2 86.4 +18.2
46 + 21 < 5 1.6 + 0.23
7
ddI 236.2 42 + 12 1.08 + 0.22 L/Kg
< 5 1.5 24
TDF 635.52 25 1.3 + 0.6 L/Kg
0.7–7.2 17 150
3TC 229.3 86 + 16 1.3 + 0.4 L/Kg
< 36 5 - 7 25
FTC 247.24 93 1.4 + 0.3 L/Kg
< 4 10 39
ABV 670.76 83 0.86 + 0.15 L/Kg
50 1.5 + 0.63
20
N/NtRTIs: basic pharmacologic features
N/NtRTIs:New drugs under development
• Abacavir ABC• Didanosine DDI• Emtricitabine FTC• Lamivudine 3TC• Stavudine D4T• Zidovudine ZDV• Zalcitabine DDC• Tenofovir TDF
-apricitabine-Amdoxovir- GS 9131 (9148)- Racivir- Elvucitabine
(?)
Peso mol.
g/mol
Biod.Orale
(%)
VD Legame Proteico
(%)
Plasma T/2(h)
Eliminazione(via principale)
EFV 315.68 nd 2.4 L/Kg > 99 45
NVP 266.3 93 1.21 L/Kg 60 25-30
ETR 435.28 nd nd 99.9 41
NNRTIs: caratteristiche farmacologiche
NNRTIs:New drugs under development
• Delavirdine DLV• Efavirenz EFV• Nevirapine NVP• Etravirine ETR
- TMC 278 (rilpivirine)- UK- 453,061 (Lersivirine)- IDX 899- RDEA 806
Drug
Efavirenz
Nevirapine
Etravirine
Cmin (ng/mL) Efficacy
** 1000-2200-3000*
3400-4300
- *
Cmin (ng/mL) Toxicity
** 4000
6000
-
* after NVP failure * pending results in nive patients with the 100 mg tablet
Reference Concentrations (Cmin) for Efficacy & Toxicity
• 154 HIV-infected patients– All taking 3-drug ART– HIV RNA in blood <50 c/mL
• HIV RNA measured using a more sensitive assay (2.5 c/mL)
– NVP: 60% <2.5 c/mL– EFV: 42% <2.5 c/mL– LPV/r: 29% <2.5 c/mL
• NVP was the only factor associated with undetectable HIV RNA on multivariate analysis
Bonora et al. J Med Virol 2009;81:400–405
0
50
40
30
20
10
NVP EFV LPV/r
HIV
RN
A (c
opie
s/m
L)
p<0.05
n 48 57 49
p<0.05
Ultrasensitive Assessment of Residual HIV Viraemia in HAART-Treated Patients With Persistently Undetectable Plasma HIV-RNA: A Cross-
Sectional Evaluation
Peso mol.g/mol
Biod. Orale (%)
VD Legame Proteico
(%)
Plasma T/2 (h)
Eliminazione(Via
principale)
APV 625.7 nd 6 L/Kg 90 7.7
IDV 711.8 65 0.4-1.7 L/Kg 60 2.0
LPV 628.8 nd nd 98-99 5-6
NFV 663.90 70-80 2-7 L/Kg > 98 3.5-5
RTV 720.95 nd 0.3-0.6 L/Kg 97 3-5
SQV 766.95 4 700 L 97 7-12
ATV 704.9 68 nd 86 8.6
TPV 602.7 nd nd > 99.9 5.5-6.0
DRV 547.7 37-82 88.1-131 L 95 15
PIs: caratteristiche farmacologiche
PIs:New drugs under development• Amprenavir
APV• Indinavir IDV• Lopinavir LPV• Nelfinavir NFV• Ritonavir RTV• Saquinavir SQV• Atazanavir ATV• FosAmprenavir fAPV• Tipranavir TPV• Darunavir DRV
- GS 8374- GRL 98065
Drug
Amprenavir
Indinavir
Lopinavir/Ritonavir
Nelfinavir
Ritonavir
Saquinavir
Atazanavir
Tipranavir
Cmin (ng/mL) Efficacy
400
100
1000
*800
2100
100-250
150
15000 - 20000 #
Cmin (ng/mL) Toxicity
-
8000-10000
-
-
2100
-
850
35000
* M8; ** Measured 8-20 hours post-dose # in case of triple drug failure
Reference Concentrations (Cmin) for Efficacy & Toxicity
DRUG + TARGET DRUG/TARGET
Keq
DRUG + TARGET DRUG/TARGETKeq
In case of reduced target affinity (by selection of mutations in the PI genome coding for PI-resistance), the same effect may be obtained by increasing drug exposure
[c] ng/mL
1 2 3 4 5 6 n. PI mutations
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
Median [c]
WT MEC
R1 MEC
R2 MEC
R3 MEC
R4 MEC
R5 MEC
R6 MEC
?
Rn
Rn MEC
How far the proportionality between the n. of PI resistance mutations and the value of MEC is maintained?
Antiretrovirals disposition is complex Intracellualr and plasma concentrations of antiretrovirals are influenced by many processes that are mediated by different transporters and enzymes.
ABCB1
TransportersABCC1ABCC2OATPs
CYP3A4
MetabolismCYP3A5CYP2B6
CYP2C19PXR
Nuclear ReceptorsCAR
PXR
CYP3A
DrugATP ADP + Pi
ABCB1
DrugATP ADP + Pi
ABCC1
Pregnane X receptor
Favourable genotypes
rho = 0.517, p = 0.0001
n = 13 n = 15 n = 24 n = 3
Number of favourable genotypes
850
150
ATV 400 QD
ATV 200 bid
Bonora S, et al. Abstr O 17Unboosted – Atazanavir (ATV) (3) ATV ng/mL
0
1200
1000
800
600
400
200
[Ctrough] gm
Below MEC (150 ng/ml)
ATV QD 6/10 pts
ATV bid
2/10 pts
plasma
ATV 400 QD
ATV 200 bid
465
745
Intracellular(PBMCs)
Peso mol.
g/mol
Biod.Orale
(%)
VD Legame Proteico
(%)
Plasma T/2(h)
Eliminazione(via principale)
ENF 4491.9 84.3* 5.5 L 92 3.8 Protein catabolism
MVC 51.3.7 23 194 L 76 13.2
EIs: caratteristiche farmacologiche
lucgag polenv
gag pol
CD4 CCR5
R5X4R5/X4 (dual)
lucgag polenv
gag pol
Luciferase expression vector
Env expressionvector library
Transfection
Infection
CD4 CXCR4Entry inhibitors added for confirmation of tropism call
Entry Inhibitors:
New drugs under development
• Enfuvirtide T-20
• Maraviroc MVC
-Vicriviroc-PRO 140-INCB009471-AMD 070-TNX-355
HIV Attachment, Co-receptor Binding, and Fusion Targets for Inhibition
Co-receptorBinding
CCR5/CXCR4(R5/X4)
CCR5 antagonistse.g. maraviroc,vicriviroc, PRO 140
Virus–CellFusion
Fusion inhibitorse.g. enfuvirtidegp41
gp120
V3 loop
CD4Binding
CD4
Cellmembrane
CD4 bindinginhibitorse.g. TNX-355
Adapted from Moore JP, et al. Proc Natl Acad Sci USA 2003;100:10598–10602
Drug
Enfuvirtide
Maraviroc
Cmin (ng/mL) Efficacy
1500-1900
100
Cmin (ng/mL) Toxicity
-
400
Reference Concentrations (Cmin) for Efficacy & Toxicity
0
Analysis of MERIT study[1]
WeeksMed
ian
CD4+
Cel
l Cou
nt Δ
Fro
m B
asel
ine
(cel
ls/m
m3 )
50
100
150
0 16 32 482 8 12 24 4020
MVC + ZDV/3TC (n = 360)
EFV + ZDV/3TC (n = 360)
151
122
P = .004 for the difference over time
4
+ 8.1%
+ 9.5%
Δ CD4+ Percentage Bonora S, et al. ICAAC 2009
Maraviroc PK is influenced by OATP1B1
OATP1B1 is a major hepatic influx transporter and its substrate specificity for MVC has been investigated.
OATP1B1 521CT correlates with higher MVC plasma concentrations, confirming the role of OATP1B1 in the disposition of MVC.
Siccardi M, et al. IWCPHT 2009
Siccardi M, et al. CROI 2010
Peso mol.
g/mol
Biod.Orale
(%)
VD Legame Proteico
(%)
Plasma T/2(h)
Eliminazione(via principale)
RAL 482.51 32 nd 83 9.0
IIs: caratteristiche farmacologiche
Integrase Inhibitors:• Raltegravir
New drugs under development
- elvitegravir- GSK 1349572
RAL efficacy is not driven by Cmin
• 16 out of 332 patients had GM observed C12hr values <33 nM (~in vitro IC95)
• These patients had a similar rate of treatment success compared to patients with other GM observed C12hr values
GM Observed C12hr (nM)
8 - 128 - 254 - 547 -
% o
f P
atie
nts
with
HIV
RN
A <
400
0
20
40
60
80
100
125 254 545 9151
GM Observed C12hr (nM)
8 - 128 - 254 - 547 -
% o
f Pat
ient
s w
ith H
IV R
NA
<40
0
0
20
40
60
80
100
125 254 545 9151
GM Observed C12hr <33 nM
Wenning et al HIV Clin Pharm Workshop 2008
Outcomes at Week 48
9785
9890 8785 83
88 88 87
0
20
40
60
80
100
120
100 mg 200 mg 300 mg 400mg EFV
<400 copies <50 copies
Virologic Efficacy
Raltegravir
CD4+ count increases similar between arms: 144-221 cells/mm3
Markowitz 2007
S/GSK1349572: Potent Virologic Suppression in 10-Day Monotherapy Study
• 10-day monotherapy study in HIV-infected patients evaluated efficacy of varying doses of S/GSK1349572[1]
– Mean maximal reduction in HIV-1 RNA during study period
• -2.5 log10 copies/mL in 50-mg dose arm
• Resistance profile distinct from that of RAL and ELV[2]
• 12-hr half-life allows QD dosing[3]
• Activity not dependent on boosting[3]
1. Lalezari J, et al. IAS 2009. Abstract TUAB105. Reproduced with permission. 2. Underwood M, et al. IAS 2009. Abstract WEPEA098. 3. Min S, et al. IAS 2009. Abstract WEPEA099.
Dosing period Follow-up period
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1(BL)
2 3 4 7 8 91011 14 21(FU)Day
Mea
n Ch
ange
Fro
m B
asel
ine
in
HIV
-1 R
NA
(log 10
c/m
L)
2 mg10 mg50 mgPBO
Mapping the RAL inhibition window
0
500
1000
1500
2000
2500
0 10 20 30 40 50
Time of RAL addition or removal (h)
Infe
cted
cel
ls/w
ell
RAL washed outat different times
RAL added atdifferent times
RAL Inhibition Window: ~4h – 12h post-infection
Persistent RAL inhibitory effect
Raltegravir Exhibits a Long Off-Rate on Complexes Assembled in vitro
T1/2 = 27 hrs at room temp
Time (min)
0 500 1000 1500 2000 2500
Frac
tion
boun
d
0.0
0.2
0.4
0.6
0.8
1.0
WT - ralN155H - ral
Letter Nature Medicine 14, 762 - 766 (2008) Published online: 15 June 2008
Dose-response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs
Lin Shen, Susan Peterson, Ahmad R Sedaghat, Moira A McMahon, Marc Callender, Haili Zhang, Yan Zhou, Eleanor Pitt, Karen S Anderson, Edward P Acosta & Robert F Siliciano
In ARVs pharmacology it is common to refer to drug potency in terms of Inhibitory quotient (IQ) LPV [c] ng/mL
WT MEC for LPV [c] ng/mL
0 12 24 Time (hours)
IQ = LPV Ctrough = 5500 ng/mL
WT MEC for LPV = 1000 ng/mL= 5,5
However, the time required to exert the effect is not considered in the IQ equation
The slope of the curve (steepness) can be incorporated in the IQ equation as m :
Log (fa/fu) = m log(D/IC50)m1 m2 m3
Log (fa/fu) = m log(D/IC50)
Fraction of the viral population affected by the drug
Fraction of the viral population unaffected by the drug
Steepness of the curve
Drug concentration
Drug concentration inhibiting the 50% of viral growth
The effect of the virus is measured in a single-
round infectivity assay in vitro as infected cells (%) rather than as HIV-RNA fall per time unit (clinical
studies)
A new index is thus termed:
Instantaneous Inhibitory Potential (IIP)
IIPCmin = log (1/fuCmin)
= log [1+ (Cmin/IC50)m]
*
Using observed failure approach: RAL 92% and EFV 91%
83%
84%
0 4 8 16 24 32 40 48 60 72 84 96Week
0
20
40
60
80
100
Pa
tien
ts W
ith H
IV-1
RN
A
< 5
0 c
op
ies/
mL
(%
)
RAL 100 mg BID.RAL 200 mg BID.RAL 400 mg BID.RAL 600 mg BID.EFV 600 mg QD
But…….
These are the facts…….
EFV
RAL
Thus…..
• This is an in vitro assay……
• Data from phase I-II monotherapy trials in humans are available…..
• Clinically determined PK/PD findings generally show a reasonable degree of consistency across all drug development phases…..
• Humans remain the best model of human disease…..
CNS-Penetration Effectiveness (CPE) Ranks
Letendre S, et al. Arch Neurol 2008; 65: 65-70Varatharajan L, Thomas SA. Antivir Res 2009; 82: A99-A109
LOW INTERMEDIATE HIGH
Tenofovir Stavudine Zidovudine
Didianosine Lamivudine Abacavir
Zalcitabine Emtricitabine Delavirdine
Nelfinavir Efavirenz Nevirapine
Ritonavir Etravirine Lopinavir
Saquinavir Darunavir Amprenavir
Tipranavir Atazanavir Indinavir
Enfuvirtide Raltegravir Fosamprenavir
Maraviroc
0 0.5 1
Letendre, S. et al. Arch Neurol 2008;65:65-70.
Subjects who had lower central nervous system Penetration-Effectiveness (CPE) ranks were more likely to have detectable cerebrospinal fluid (CSF) viral load when CPE rank was analyzed
as a continuous variable (A) or as a categorical variable (B)
0% 100% 200% 300% 400% 500%
APV (20%)
NVP (80%)
APV (50%)
ABC (40%) ABC (150%) Female genital tract exposure
ZDV (200%)
IDV (200%)TDF (400%)
3TC (400%)
Nonnucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Nucleoside Reverse Transcriptase Inhibitors
LPV (30%)
ATV (30%)
FTC (600%)EFV (0.6%)
LPV (5%)
EFV (3%)
IDV (100%)
NVP (70%)
TDF (500%)
3TC (600%)
ZDV (200%)
ABC (150%)
Male genital tract exposure
By courtesy of A. Kashuba
RAL (645%)
• Greater CYP450 enzyme inhibition specificity
• Less induction of drug metabolizing enzymes and transporters
Keys to Pharmacoenhancement
1 100
20
40
60
80
100
RTV
GS-9350
hPXR Activation
Concentration (µM)
Resp
onse
(%E m
ax)
Induction of Hepatocyte CYP3A4 mRNA
mean + SD, n=3
0
20
40
60
80
100
120
1 µM 3 µM 10 µM 30 µM Rifampicin
GS-9350
% M
axim
um
mean ± SD, n=3
CYP450 enzyme IC50
(µM)1A2 2B6 2C8 2C9 2C19 2D6 3A*
GS-9350 >25 2.8 30 >25 >25 9.2 0.2
RTV >25 2.9 5.5 4.4 >25 2.8 0.2
* midazolam 1’-hydroxylase (no preincubation)mean of 3 experiments conducted in duplicate
Acknowledgments
THE UNIVERSITY
of LIVERPOOL
TORINO:
Stefano Bonora
Antonio D’Avolio
Mauro Sciandra
Marco Siccardi
Daniel Gonzalez de Requena
Alessandro Sinicco
Sabrina Audagnotto
Cristina Tettoni
Laura Trentini
Andrea Calcagno
Anna Lucchini
Agostino Maiello
Ivan Dal Conte
LIVERPOOL:
David Back
Saye Khoo
Andy Owen
LONDON:
Marta Boffito
Anton Pozniak
ROMA:
Andrea Antinori
Emanuele Nicastri
Giuseppe Ippolito