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Interactions between ARVs and DAAs
David M. Burger Professor of Clinical Pharmacy
Radboud University Nijmegen Medical Center The Netherlands
d.burger@akf.umcn.nl
Outline
• Description of PK profiles of DAAs
• Interpretation of interpatient PK variability & PK/PD relationships
• Review of ARV – DAA interactions, based on: • Clinical data • Theoretical assumptions
• Conclusions
BOC & TVR PK profile
BOC TVR
Route of Metabolism AKR1C2 + 1C3, CYP3A CYP3A
Transporter effects P-gp substrate not an OATP1B1
substrate
P-gp substrate
In vitro CYP inhibition effects
CYP3A (not CYP1A2, 2A6, 2B6, 2C8,
2C9, 2C19, 2D6, or 2E1)
CYP3A (not 1A2, 2C9, 2C19, or 2D6)
In vitro CYP induction effects
Does not induce CYP1A2, 2B6, 2C8,
2C9, 2C19, 3A
Low potential to induce CYP2C, 3A, or 1A
In vitro transporter inhibition effects
P-gp*, OATP1B1, BCRP, not MRP2
P-gp
Protein Binding 68-75% 59-76% *conflicting, prescribing information “potential”, Chu X AASLD 2011 “BOC did not inhibit P-gp”
Slide courtesy of Dr Jennifer Kiser
Telaprevir & boceprevir are CYP3A substrates: boosting by ritonavir?
Kempf et al. Antiviral Chem Chemother 2007
BOC + RTV
BOC TVR
TVR + RTV
Interpatient variability & PK/PD relationships: important for interpretation of drug-drug interactions (1)
• Telaprevir phase 1B study (Reesink et al. Gastroenterol 2006)
Dose Mean Cmin (mg/L) HCV-RNA decline in 14days
450mg q8h 0.781 ≥ 3 log10 750mg q8h 1.054 ≥ 4 log10
1250mg q12h 0.676 ≥ 3 log10
Interpatient variability & PK/PD relationships: important for interpretation of drug-drug interactions (2)
Victrelis, clinical pharmacology review Available at www.fda.gov
Interpatient variability & PK/PD relationships: important for interpretation of drug-drug interactions (3)
Victrelis, clinical pharmacology review Available at www.fda.gov
Interpatient variability & PK/PD relationships: important for interpretation of drug-drug interactions (4)
Victrelis, clinical pharmacology review Available at www.fda.gov
Summary of PK/PD relationships
• Dose-finding studies indicate Cmin is most important PK parameter to predict response
• The “average patient” will have DAA exposure on the maximum plateau but how much of the failures is explained by PK?
• Phase III studies exclude patients with potential negative effect on DAA exposure
• Generally, interpatient variability in PK in clinical practice is larger than in phase III studies (food, co-medication, adherence)
• Therapeutic range for DAAs currently unknown
Overview of drug-drug interaction studies (published or presented)
1. Effect of telaprevir on PK of ARVs
2. Effect of ARVs on telaprevir PK
3. Effect of boceprevir on PK of ARVs
4. Effect of ARVs on boceprevir PK
A priori expected interactions between ARVs - DAAs
1. DAAs are CYP3A substrates → [DAA]↑ with RTV-boosted HIV PIs
2. DAAs are CYP3A substrates → [DAA]↓ with NNRTIs
3. DAAs are CYP3A inhibitors → [HIV PI/r]↑ (super-boosting)
Overview of drug-drug interaction studies (published or presented)
1. Effect of telaprevir on PK of ARVs
2. Effect of ARVs on telaprevir PK
3. Effect of boceprevir on PK of ARVs
4. Effect of ARVs on boceprevir PK
R van Heeswijk,1 A Vandevoorde,1 G Boogaerts,1 T Vangeneugden,1 E de Paepe,1 R Polo,1 R Van Solingen-Ristea,1 K de Backer,1 V Garg,2 and M Beumont1 1Tibotec BVBA, Beerse, Belgium; 2Vertex Pharmaceuticals Incorporated, Cambridge, MA, USA
Pharmacokinetic Interactions Between Antiretroviral Agents and the Investigational HCV Protease Inhibitor Telaprevir in Healthy Volunteers
van Heeswijk R, et al. 18th CROI 2011. Abstract 119
Mean HIV PI PK Profiles
0 2 4 6 8 10 12 0 2 4 6 8 10 12
LPV/r ATV/r
DRV/r fAPV/r
AUC
AUC 47% AUC 40%
AUC 17%
n=19
n=11
n=20 n=16
n=12 n=7
n=11 n=18
Time (hours)
0
4000
8000
12000
LPV
conc
entr
atio
n (n
g/m
L)
0 2 4 6 8 10 12
ATV
conc
entr
atio
n (n
g/m
L)
0 6 12 18 24 Time (hours)
4000
3000
2000
1000
0
Time (hours)
DR
V co
ncen
trat
ion
(ng/
mL)
6000
4000
2000
0
APV
conc
entr
atio
n (n
g/m
L)
Time (hours)
4000
3000
2000
1000
0
PI alone PI + TVR
APV = amprenavir
PI alone PI + TVR
PI alone PI + TVR
PI alone PI + TVR
Mean HIV PI PK Profiles
0 2 4 6 8 10 12 0 2 4 6 8 10 12
LPV/r ATV/r
DRV/r fAPV/r
AUC
AUC 47% AUC 40%
AUC 17%
n=19
n=11
n=20 n=16
n=12 n=7
n=11 n=18
Time (hours)
0
4000
8000
12000
LPV
conc
entr
atio
n (n
g/m
L)
0 2 4 6 8 10 12
ATV
conc
entr
atio
n (n
g/m
L)
0 6 12 18 24 Time (hours)
4000
3000
2000
1000
0
Time (hours)
DR
V co
ncen
trat
ion
(ng/
mL)
6000
4000
2000
0
APV
conc
entr
atio
n (n
g/m
L)
Time (hours)
4000
3000
2000
1000
0
PI alone PI + TVR
APV = amprenavir
PI alone PI + TVR
PI alone PI + TVR
PI alone PI + TVR
Effect of TVR on RAL exposure
Van Heeswijk et al. 51st ICAAC, poster 1738a
AUC: +31%
Infectious Diseases & Vaccines Therapeutic Area
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Pharmacokinetic interaction between etravirine or rilpivirine and telaprevir in healthy volunteers: a randomised, two-way crossover trial
TN Kakuda, L Leopold, S Nijs, A Vandevoorde, H Crauwels, K Bertelsen, M Stevens, J Witek, Y van Delft, F Tomaka, RMW Hoetelmans
13th International HIV Clinical Pharmacology Workshop Barcelona, Spain, April 2012 [abstract O_18]
Infectious Diseases & Vaccines Therapeutic Area
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Time (h)
0 2 4 6 8 10 12
ETR
pla
sma
conc
entra
tion
(ng/
mL)
0
200
400
600
800
1000
1200
1400ETR aloneETR + TVR
Mean (SD) etravirine plasma concentration over time, with or without telaprevir
19
TVR AUC: -6%
Infectious Diseases & Vaccines Therapeutic Area
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Time (h)
0 4 8 12 16 20 24
RP
V p
lasm
a co
ncen
tratio
n (n
g/m
L)
0
50
100
150
200
250
300
350
400RPV aloneRPV + TVR
Mean (SD) rilpivirine plasma concentration over time, with or without telaprevir
20
TVR TVR AUC: +79%
Overview of drug-drug interaction studies (published or presented)
1. Effect of telaprevir on PK of ARVs
2. Effect of ARVs on telaprevir PK
3. Effect of boceprevir on PK of ARVs
4. Effect of ARVs on boceprevir PK
Mean TVR PK Profiles
AUC = area under the curve
AUC 54% AUC 20% AUC 32% AUC 35%
TVR alone
TVR + ARV
n=14 n=17 n=16 n=20
n=12 n=14 n=11 n=18
Time (hours)
0
1000
2000
3000
TVR
con
cent
ratio
n (n
g/m
L)
LPV ATV DRV fAPV
0 2 4 6 8 0 2 4 6 8
0 2 4 6 8 0 2 4 6 8
Mean TVR PK Profiles
AUC = area under the curve
AUC 54% AUC 20% AUC 32% AUC 35%
TVR alone
TVR + ARV
n=14 n=17 n=16 n=20
n=12 n=14 n=11 n=18
Time (hours)
0
1000
2000
3000
TVR
con
cent
ratio
n (n
g/m
L)
LPV ATV DRV fAPV
0 2 4 6 8 0 2 4 6 8
0 2 4 6 8 0 2 4 6 8
EFV + TVR: the effect of a TVR dose increase
0
1000
2000
3000
4000
0 2 4 6 8 10 12
TVR 750 mg q8h (n=20, reference)
TVR 1500 mg q12h + E/T (n=16) TVR 1125 mg q8h
+ E/T (n=15)
Time (hours)
TVR
con
cent
ratio
n (n
g/m
L)
TVR dose
Effect of EFV/TDF on TVR Cmin Cmax AUC8h
1125 mg q8h 0.75 (0.66–0.86) 0.86 (0.76–0.97) 0.82 (0.73–0.92)
1500 mg q12h 0.52 (0.42–0.64) 0.97 (0.88–1.06) 0.80 (0.73–0.88)*
*Average steady state plasma concentration (Cssaverage)
AUC 18% AUC 20%
Effect of RAL on TVR exposure
Van Heeswijk et al. 51st ICAAC, poster 1738a
AUC: +7%
Infectious Diseases & Vaccines Therapeutic Area
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Time (h)
0 2 4 6 8
TVR
pla
sma
conc
entra
tion
(ng/
mL)
0
1000
2000
3000
4000
5000TVR aloneTVR + ETR
Mean (SD) telaprevir plasma concentration over time, with or without etravirine
26
AUC: -16%
Infectious Diseases & Vaccines Therapeutic Area
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Time (h)
0 2 4 6 8
TVR
pla
sma
conc
entra
tion
(ng/
mL)
0
1000
2000
3000
4000
5000TVR aloneTVR + RPV
Mean (SD) telaprevir plasma concentration over time, with or without rilpivirine
27
AUC: -8%
Summary of TVR – ARV interactions HIV drug Effect on
ARV AUC Effect on TVR AUC
Can be used? Reference
EFV* -7% -18% Yes Van Heeswijk et al. CROI 2011
ETR -6% -16% Yes Kakuda et al. HIV PK 2012
RPV +79% -8% Yes Kakuda et al. HIV PK 2012
ATV/r +17% -20% Yes Van Heeswijk et al. CROI 2011
DRV/r -40% -35% No Van Heeswijk et al. CROI 2011
FPV/r -47% -32% No Van Heeswijk et al. CROI 2011
LPV/r +6% -54% No Van Heeswijk et al. CROI 2011
RAL +31% +7% Yes Van Heeswijk et al. ICAAC 2011
TDF +30% 0% Yes Van Heeswijk et al. ICAAC 2008
*TVR dose 1125mg q8h
Some comments on TVR – ARV drug interaction data
• Some results were expected: • EFV induces TVR CYP3A metabolism • RPV does not induce TVR CYP3A metabolism • TVR inhibits RPV CYP3A metabolism • RAL does not interact with TVR
• Some other results are more difficult to explain:
• How does TVR increase TDF levels? • Why do RTV-boosted PIs not inhibit TVR metabolism? • How can TVR reduce levels of some RTV-boosted PIs? • Why is ATV different?
Overview of drug-drug interaction studies (published or presented)
1. Effect of telaprevir on PK of ARVs
2. Effect of ARVs on telaprevir PK
3. Effect of boceprevir on PK of ARVs
4. Effect of ARVs on boceprevir PK
BOC effect on HIV PIs
Hulskotte et al. CROI 2012; abstract 772LB
HIV drug Effect on ARV AUC
ATV/r -35% LPV/r -34% DRV/r -44%
BOC effect on HIV PIs
Hulskotte et al. CROI 2012; abstract 772LB
HIV drug Effect on ARV AUC
ATV/r -35% LPV/r -34% DRV/r -44%
Boceprevir & Raltegravir
De Kanter et al. CROI 2012; abstract 772LB
HIV drug Effect on ARV AUC
Effect on BOC AUC
RAL +1% +7%* * vs. historical controls
Kyle P. Hammond, Pamela Wolfe, James R. Burton, Julie A. Predhomme, Christine M. Ellis, Michelle L. Ray,
Lane R. Bushman, Jennifer J. Kiser University of Colorado Denver kyle.hammond@ucdenver.edu
13th International Workshop on Clinical Pharmacology of HIV Therapy
April 18, 2012 Abstract: O_15
Pharmacokinetic interaction between boceprevir and etravirine in HIV/HCV
seronegative volunteers
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Etravirine Results Differ From Hypothesis
Mean (CV %)
AUC(0,τ)
(ng*h/mL) Cmax
(ng/mL) Cmin
(ng/mL)
ETV alone 7698 (33%)
900 (29%) 439
(46%)
ETV + BOC 5957 (54%)
686 (45%) 313
(69%) GMR
(ETV + BOC vs.
ETV alone)
0.77 0.76 0.71
Percent change
↓ 23% ↓ 24% ↓ 29%
90% CI 0.66-0.91 0.68-0.85 0.54-0.95
• CL/F and V/F GMR were 1.29 (p=0.112) and 1.33 (p=0.0315), respectively.
• T1/2 not statistically different p=0.738
Overview of drug-drug interaction studies (published or presented)
1. Effect of telaprevir on PK of ARVs
2. Effect of ARVs on telaprevir PK
3. Effect of boceprevir on PK of ARVs
4. Effect of ARVs on boceprevir PK
HIV drug Effect on BOC AUC
ATV/r -5%
LPV/r -34%
DRV/r -32%
Summary of BOC – ARV interactions
Hulskotte et al. CROI 2012; abstract 772LB
HIV drug Effect on BOC AUC
ATV/r -5%
LPV/r -34%
DRV/r -32%
Summary of BOC – ARV interactions
Hulskotte et al. CROI 2012; abstract 772LB
Kassera et al. CROI 2011
Presented at the 13th Int. Workshop on Clin. Pharmacology of HIV Pharmacology – 2012, Barcelona Spain
Effect of ETR on BOC Mean (CV%)
AUC(0,τ)
(ng*h/mL) Cmax
(ng/mL) C8
(ng/mL) BOC 4601 (47%) 1423 (43%) 106 (64%)
BOC + ETV 5047 (30%) 1565 (28%) 94 (98%) GMR (BOC + ETV
vs. BOC) 1.10 1.10 0.88
Percent Change ↑ 10% ↑ 10% ↓ 12%
90% CI 0.94-1.28 0.94-1.29 0.66-1.17
• CL/F and V/F GMR were 0.91 (p=0.3161) and 0.84 (p=0.3276) • Difference in t1/2 was not statistically different as well p=0.6771
HIV drug Effect on ARV AUC
Effect on BOC AUC
Can be used? Reference
TDF +5% +8% Yes Kassera et al. CROI 2011
EFV +20% -19% No Kassera et al. CROI 2011
ETR -23% +10% Yes Hammond et al. HIV PK 2012
ATV/r -35% -5% No Hulskotte et al. CROI 2012
LPV/r -34% -34% No Hulskotte et al. CROI 2012
DRV/r -44% -32% No Hulskotte et al. CROI 2012
RAL +1% +7%* Yes De Kanter et al. CROI 2012
* vs. historical controls
Summary of BOC – ARV interactions
Some comments on BOC – ARV drug interaction data
• Some results were expected: • EFV induces BOC CYP3A metabolism • RAL does not influence BOC metabolism
• Some other results are more difficult to explain:
• How can BOC reduce ETR levels? • Why does ETR not induce BOC metabolism? • Why do RTV-boosted PIs not inhibit BOC metabolism? • How can BOC reduce levels of some RTV-boosted
PIs? • Why is ATV different?
Translation of phase I healthy volunteer data to the clinic
• Phase II studies in co-infected patients (CROI 2012): • Dieterich et al.: TVR + ARVs with no interactions • Sulkowski et al. BOC + ARVs with some interactions • Both studies showed adequate HCV and HIV response
• Potential explanations for this apparent discrepancy:
• Drug levels in co-infected patients are higher than in healthy subjects; 30-50% decrease may have no impact
• Phase II studies with multiple ARVs are in fact a series of underpowered phase Ib studies
• IFN-α effect? Free concentrations? Intra-hepatocyte levels?
Sulkowski et al. CROI 2012
Potential conclusions from this study: •BOC is not needed in patients on ATV/r ???? •PR has no activity in patients on LPV/r or DRV/r ????
Conclusions
• Drug-drug interactions with DAAs are here to stay • Currently more data how to combine TVR with HIV medications than
for BOC (but TVR may be more problematic than BOC with non-HIV medications)
• ANRS & ACTG are enrolling co-infected patients in new studies • Some newer DAAs may be easier to combine with ARVs (more data)
• Rapidly evolving field: make sure you are updated by:
• Check www.hep-druginteractions.org • Consult a clinical pharmacologist/pharmacist • Read a review, e.g.,
• Seden & Back: DAAs for hepatitis C and ARVs; potential for drug-drug interactions. Curr Opinion HIV AIDS 2011;6; 514-26
• Kiser et al. Review and management of drug interactions with boceprevir and telaprevir. Hepatology 2012; 55(5): 1620-8.
Acknowledgements
• Rolf van Heeswijk & Thomas Kakuda (Johnson & Johnson)
• Joan Butterton (Merck) • Jürgen Rockstroh • Jennifer Kiser
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