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Pharmacological determinants oflong-term treatment success
Professor David BackLiverpool, UK
Pharmacological Issues withAntiretroviral Therapy
• Intrinsic potency
• Bioavailability
• Effect of food and otherdrugs on absorption
• Protein binding
• Plasma half-life
• Intracellular half-life
• Intracellular activation
• Sanctuary sites
• Drug interactions
w unfavourable
w pharmacoenhancement
• Tolerability and toxicity
• Dosage regimens inspecial patient groups
Three Key Parameters
• Potency of drug against the virus
• Protein binding– must have adequate concentrationin vivo of free drug
• In vivo pharmacokinetics(Cmax, Cmin, AUC, half-life)
Activation of Nucleoside Analogues
Adenosine
ddAddA-TP-TP
ddI - MP
ddA-MP
ddA-DP
ddI5’5’ Nucleotidase Nucleotidase
AdenylateAdenylate Synthetase Synthetase& Adenylate& Adenylate Lyase Lyase
Adenylate Kinase &Adenylate Kinase &PRPPPRPP Synthetase Synthetase
Adenylate Kinase &Adenylate Kinase &PRPPPRPP Synthetase Synthetase
Guanosine
ABC- MP
CBV-MP
CBV-DP
CBV-TPCBV-TP
ABCAdenosineAdenosine
PhosphotransferasePhosphotransferase
CytosolicCytosolic Enzyme Enzyme
KinaseKinase
KinaseKinase
Thymidine
ZDV-MP
ZDV
ZDV-DP
ZDV-TPZDV-TP
d4T
d4T-MP
d4T-DP
d4T-TPd4T-TP
ThymidylateThymidylate Kinase Kinase
NDP KinaseNDP Kinase
Thymidine KinaseThymidine Kinase
Cytidine
ddC 3TC
ddC-MP
ddC-DP
ddC-TPddC-TP
3TC-MP
3TC-DP
3TC-TP3TC-TP
NDP KinaseNDP Kinase
CMP/CMP/Dcmp Dcmp KinaseKinase
Deoxycytidine Deoxycytidine KinaseKinase
Metabolic Pathways of Cellular Nucleosides
IMP
GMP
GDP
dGDP
dGTP
ADP
dADP
dATP
AMP
dCMP
dCDP
dCTP dTTP
Thymidine
dUMP dTMP
dTDP
CytidineRBVRBV
CDPHUHU
HUHU
DPDDPD
11
22 22
33
1. IMP dehydrogenase 2. Ribonucleotide reductase 3. Carrier-mediated transport
De NovoPathway
Salvage Pathway(<20%)
MAMA
MRP4: A previously unidentified factor inresistance to nucleoside-based antiviral drugs
“Because MRP is expressed in normal tissues and
because HIV can infect a variety of cell types, high
levels of MRP4 expression at some anatomical sites
may allow growth and evolution of drug-resistant HIV
by decreasing the amount of intracellular drug to
levels below that necessary to inhibit HIV replication.”
Schuetz et al.Nature Medicine, September 1999
Organ Distribution of Transport Proteins
Brain MDR1 OAT3 MRP1 OATP1 MRP5 OATP2
Kidney MDR1 OATP1 MRP1 OATP2 NTCP1 OCT1 OAT1 OCT2 OAT3
Liver LST1 OAT2 MDR1 OAT3 MRP2 OATP1 MRP3 OCT1 NTCP1 SPGP
LymphocytesMDR1MRP4
Pharmacokinetic profile of a single PI administeredtwice daily and efavirenz given once daily
0 6 12 18 24
Time (h)
Pla
sma
Co
nce
ntr
atio
n
PI
EFV
IC95
Area of Potential Replication
NV 15107 StudySelection of Doses
AUC0–24h (µg.h.L-1)
Pea
k re
du
ctio
n in
HIV
-1 R
NA
(lo
g10
co
pie
s/m
l)
– 4
– 3
– 2
– 1
0
1
0 20,000 40,000 60,000 80,000
Fortovase 400 mg tid
Fortovase 800 mg tid
Fortovase 1200 mg tid
Relationship between peak reduction in plasma HIV RNAand SQV AUC0-24h for hard and soft gel formulations
AUC0–24h (µg.h.L-1)
Pea
k re
du
ctio
n in
HIV
-1 R
NA
(lo
g10
co
pie
s/m
l)
– 4
– 3
– 2
– 1
0
1
0 20,000 40,000 60,000 80,000
Hard gel Soft gel
EC50 = 3226 µg.h.L-1
Emax = -1.79 log10 copies/ml
Gieschke et al., 1999
Target Concentration
• Exposure target of approximately 20,000 µg.h.L-1
with maximal virological response.
• Target exposure may differ depending on
concomitant therapy and patient population.
• Exposure-response modelling gave the optimal
dose of SQV sgc of 1200 mg tid.
VIRADAPT
Design
• Retrospective analysis
• 81 subjects; all received PI in salvage regimen
• At least 3 samples available for analysis
Results• Negative correlation between drug concentration and VL
• Patients subdivided:
Optimal Concentration Suboptimal ConcentrationCtrough >IC50 on Ctrough <IC50 on
2 or more occasions 2 or more occasions
-1.23 log at 48 weeks -0.24 log at 48 weeks
Arguments for TDM of PIs
• Low plasma concentrations correlate with clinical failure
• Marked inter-individual variability in plasma drug concentrations
• Complex drug interactions
• High plasma concentrations may correlate with toxicity
• PI disposition affected by liver dysfunction
• Assessment of poor adherence in selected patients
• Cost of therapy
Potential Problems with TDM
• Relatively small data sets giving concentration-responserelationships
• Target PI concentrations largely defined from in vitrostudies with exposure to single PI? Antiretrovirals in combination
• Changing patterns of adherence
• What measure is best ?w AUCw Troughw Trough and peak
Indinavir tds vs bd dosing
0.01
0.1
1
10
100
0 2 4 6 8 10 12
Time (h)
Pla
sma
Ind
inav
ir (
µg
/ml)
0.1 µg/ml(100 ng/ml)
Effect of ritonavir (100 mg)on indinavir pharmacokinetics
0.1
1
10
100
0 2 4 6 8 10 12Time (h)
Pla
sm
a I
nd
ina
vir
(µ
g/m
l)
IND (n=6)
IND + 100 mg RIT
ABT-378
0.001
0.01
0.1
1
10
0 4 8 12 16 20 24
Time (h)
Pla
sma
AB
T-3
78 (
µg
/ml)
Alone
+ 50 mg RIT
EC50
(WT, 50% HS)
Sham et al., 1998
Efavirenz(SUSTIVA , STOCRIN )
NH
O
O
F3 C CCl
C
Efavirenz – Summary of Pharmacokinetics
• Good oral absorption; can be given without regard to food
• Half-life 40–55 h; allows once daily dosing
• Highly protein bound (99.5%), but penetrates CSF
• Metabolised by CYP3A4 (also CYP2B6)
• Induces CYP3A4 (also autoinduction)
• Inhibits CYP3A4
• Renal excretion as glucuronide conjugate
Efavirenz Mean Plasma Concentration
0
2
4
6
8
10
12
14
16
0 6 12 18 24
Time (h)
EF
V P
lasm
a C
on
cen
trat
ion
(µ
M)
AUC0-t= 248 µmol.L-1.h
Cmax = 15.7 µmol.L-1
t1/2 ~ 50 h
Efavirenz “Free” Plasma Concentration
0
10
20
30
40
50
60
70
80
0 6 12 18 24
Time (h)
EF
V P
lasm
a C
on
cen
trat
ion
(n
M) Protein Binding = 99.5%
IC95 of WT & clinical isolates = 0.5–10 nM
IC95 ofWT
IC95 ofK103N
Time
Pla
sma
Co
nce
ntr
atio
n
Pharmacokinetic-Surrogate Relationship
MIC
Cmax
AUC
T > MIC
AUIC = AUC/MIC
Population Pharmacokinetics of Efavirenz
0
2
4
6
8
10
12
14
0 1 2
Pre
dic
ted
24
h
EF
V p
las
ma
co
nc
en
tra
tio
n (
µM
)
Non-Failure Failure0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 5 10 15 20 25
Pro
bab
ility
of
Su
cces
s
Predicted 24 hEFV plasma concentration (µM)
Efavirenz – Induction & Inhibition
CYP3A4
SQVSQV
SQVSQV
EFVEFV
EFVEFV
CYP3A4INDUCED
EFVEFV
EFVEFV
NLFNLF
NLFNLF
CYP3A4INDUCED
+ EFVIncrease in
SQV metabolism(AUC ↓ 60%)
+ EFVDecrease in
NLF metabolism(AUC ↑ 20%)
CONTROL
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