clinical case discussion on drug-drug interactions in hcv...

Clinical Case Discussion on Drug-Drug Interactions in HCV therapy

(HIV/HCV co-infection)

David M. Burger Professor of Clinical Pharmacy

Radboud University Nijmegen Medical Center The Netherlands

[email protected]

Outline

• Description of PK profiles of DAAs (assuming PK profiles of ARVs are known)

• Interpretation of interpatient PK variability & PK/PD relationships

• Review of ARV – DAA interactions, based on: • Clinical data or theoretical assumptions • Summary

• Conclusions

BOC & TVR PK profile

BOC TVR

Route of Metabolism AKR1C2 + 1C3, CYP3A CYP3A

Transporter effects P-gp substrate P-gp substrate

In vitro CYP inhibition effects

CYP3A CYP3A

In vitro CYP induction effects

None Low potential to induce CYP2C, 3A, or 1A

In vitro transporter inhibition effects

P-gp, OATP1B1, BCRP P-gp

Protein Binding 68-75% 59-76% Slide courtesy of Dr Jennifer Kiser (modified)

Interpatient variability & PK/PD relationships: important for interpretation of drug-drug interactions (1)

Victrelis, clinical pharmacology review Available at www.fda.gov

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)

Studies with telaprevir

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 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 TVR on RAL exposure

Van Heeswijk et al. 51st ICAAC, poster 1738a

AUC: +31%

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

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 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

18

TVR TVR AUC: +79%



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

19

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?

Studies with boceprevir

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%

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

Boceprevir & Raltegravir

De Kanter et al. CROI 2012; abstract 772LB


Effect on BOC AUC

RAL +1% +7%* * vs. historical controls

Kassera et al. CROI 2011


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% Yes/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?

Some more words on ATV/r – BOC combination

• The only boosted PI with minimal effect on BOC levels • BOC reduced ATV AUC by 35%, Cmin by 49%

• Still active against wild-type HIV? • Therapeutic drug monitoring?

• FDA/EMA have issued different warnings:

• FDA: “not recommended”

• EMA: “Co-administration of Victrelis with ritonavir-boosted atazanavir may be considered on a case-by-case basis if deemed necessary in patients with suppressed HIV viral loads and with an HIV strain without any suspected resistance to the HIV regimen. Increased clinical and laboratory monitoring is warranted.”

Preferred ARVs for combined HIV/HCV treatment based on phase I studies in healthy volunteers

Raltegravir Rilpivirine Etravirine Atazanavir/rtv

Raltegravir Etravirine (Atazanavir/rtv)

Telaprevir

Boceprevir

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

• IFN-α effect? Free concentrations? Intra-hepatocyte levels? • Phase II studies with multiple ARVs are in fact a series of

underpowered phase Ib studies

PK data of HIV PIs in 2 patients on BOC

• Patient 1 with liver cirrhosis is on DRV/r 800/100mg QD; after addition of BOC trough level of DRV is 3.8 mg/L (normal: 1.1 mg/L)

• Patient 2 with liver cirrhosis is on FPV/r 700/100mg BID; after addition of BOC trough level of APV is 1.7 mg/L (normal: 1.8 mg/L)

• These data (limited N) suggest that cirrhosis may indeed compensate for any negative effect of BOC

Schwarze-Zander & Rockstroh, AIDS 2012, in press

Therapeutic drug monitoring

• Well established for ARVs (Liverpool)

• For HCV agents TDM is currently in development • Therapeutic range unknown • Technical issues around stability • It’s too early for dose adjustments of DAAs based on

TDM

• Contact your clinical pharmacologist for advice on special cases

Other HCV agents in phase III: drug interactions?

• TMC-435: CYP3A substrate & CYP3A/CYP1A2 inhibitor

• BI-201335: CYP3A inhibitor & substrate (?)

• BMS-790052 (daclatasvir): CYP3A substrate, no CYP3A inhibitor; PgP substrate & inhibitor

• BMS-650032 (asunaprevir): CYP3A substrate & inducer; CYP2D6 inhibitor; OATP1B substrate; PgP inhibitor

• GS-7977: no interactions expected (nucleoside)

All agents being tested with (some) ARVs prior to phase II/III

Acknowledgements

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

• Joan Butterton (Merck) • Rick Bertz (BMS) • Jürgen Rockstroh • Jennifer Kiser

clinical case discussion on drug-drug interactions in hcv...

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