Interactions between ARVs and DAAsregist2.virology-education.com/2012/8coin/docs/07_Burger.pdf ·...

Interactions between ARVs and DAAs

David M. Burger Professor of Clinical Pharmacy

Radboud University Nijmegen Medical Center The Netherlands

[email protected]

mailto:[email protected]

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


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)






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]



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%



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%






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%



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%



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?






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



ATV/r -35% LPV/r -34% DRV/r -44%

Boceprevir & Raltegravir

De Kanter et al. CROI 2012; abstract 772LB


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 [email protected]

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

mailto:[email protected]


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






HIV drug Effect on BOC AUC

ATV/r -5%

LPV/r -34%

DRV/r -32%

Summary of BOC – ARV interactions


HIV drug Effect on BOC AUC

ATV/r -5%

LPV/r -34%

DRV/r -32%



Kassera et al. CROI 2011


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


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


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.

http://www.hep-druginteractions.org/

Acknowledgements

• Rolf van Heeswijk & Thomas Kakuda (Johnson & Johnson)

• Joan Butterton (Merck) • Jürgen Rockstroh • Jennifer Kiser

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