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Slide 1
Interaction profile of the new DAAs
David Back
University of Liverpool
UK
David Back
University of Liverpool
June 8th 2012
Why worry about Drug – Drug Interactions
(DDIs) in managing HCV patients?
Current interactions (limited) involving pegylated
interferon/ribavirin are well documented.
However the DAAs have increased potential for DDIs
An Interaction can alter the exposure of either the DAA or
a co-medication
– Concern is i) loss of antiviral efficacy or toxicity and ii)
loss of efficacy or toxicity of co-medication.
DDI: drug–drug interaction; HCV: hepatitis C virus
Enzyme inhibition and induction: effect of introducing
another drug when steady state has already been reached
1 2 3 4 5 6 7 8 9 10 11 12
Dru
g C
on
c.
Days
Inhibiting Drug
Enzyme Inhibition Enzyme Induction
Dru
g C
on
c.
Days
1 2 3 4 5 6 7 8 9 10 11 12
Inducing Drug
Understanding the disposition of the
currently licensed DAAs
Drug Dosing
regimen
CYP
metabolism
Non-CYP
metabolism
P-gp
Transporter
Telaprevir
Q8h
Taken with food
(20 g of fat)
CYP 3A4:
Metabolised
by
Markedly
Inhibits
– Substrate
Inhibitor
Boceprevir 3 x daily
Taken with food
CYP 3A4:
Metabolised
by
Markedly
Inhibits
AKR
Metabolise
d by
Substrate
Telaprevir EU SmPC; Boceprevir EU SmPC
Kassera C, et al. CROI 2011. Abstract 118; Garg V, et al. CROI 2011. Abstract 629
AKR: aldo-keto reductase; DAA: direct-acting antiviral
Q8h: every 8 hours; RTV: ritonavir; tid: three times daily
Telaprevir and Boceprevir are metabolised
by and inhibit CYP3A4
CYP 3A isozymes involved in the
metabolism of majority of drugs CYP 3A isozymes are the
most abundant in the liver
Proportion of total CYP enzymes
present in human liver
Proportion of drugs that are
substrates for major CYP enzymes
CYP 1A2
CYP 2A6 CYP 2B6
CYP 2C8
CYP 2C9
CYP 2C19
CYP 2D6
CYP 2E1
CYP 3A
CYP 1A2
CYP 2A6
CYP 2B6 CYP 2C8
CYP 2C9 CYP 2C19
CYP 2D6
CYP 2E1 CYP 3A
Hacker MP, et al. Pharmacology: Principles and Practice. Academic Press 2009
CYP: cytochrome P450
All percentages are approximate. For illustrative purposes,
hepatic CYP enzymes present at <5% are all represented as 3.3%
Drugs can be metabolised in the
Gastrointestinal tract and Liver
Small Intestines Liver
Adapted from Bailey DG, et al. Br J Clin Pharmacol. 1998:46:101–10 P-gp: P-glycoprotein
CYP3A
Pgp
CYP3A
Telaprevir & Boceprevir increase exposure
to CYP3A substrates: Perpetrator
Drug TVR effect on the
AUC (exposure)
BOC effect on the
AUC (exposure)
Cyclosporine A
4.6-fold increase 2.7-fold increase
Tacrolimus
70-fold increase 17-fold increase
Midazolam 3.4-fold increase (i.v)
9-fold increase (oral) 6.3-fold increase (oral)
Atorvastatin 7.9-fold increase 2.3-fold increase
Garg V, et al. Heptatology 2011:54:20–27; Garg V, et al. J Clin Pharmacol 2012 ; Lee JE, et al. Antimicrob Agents Chemother 2011;55:4569–74;
Telaprevir EU SmPC; Hulskotte EGJ et al HEPDart 2011; Abs 122 and Abs 123; Kessara C et al, CROI 2011, Abs 118; Boceprevir EU SmPC
Manageable
Difficult to manage
CI CI
CI Dose reduce
Telaprevir & Boceprevir decrease exposure
to other CYP-metabolised drugs:
Perpetrator
Co-medication
TVR effect BOC effect
AUC AUC
Escitalopram (SSRI)
Metabolised by CYP2C19 35%
21%
van Heeswijk R, et al. IWCPHT 2010. Abstract 12; Telaprevir EU SmPC; Hulskotte EGJ et al HEP Dart 2011; Abs 121; Boceprevir EU SmPC.
Mechanism: Not clearly determined
Doses may need to be increased when combined with telaprevir; but
dose adjustment not anticipated with boceprevir.
Telaprevir & Boceprevir decrease exposure
to other CYP-metabolised drugs:
Perpetrator
Garg V, et al. IWCPHT 2011. Abstract PK_17Telaprevir EU SmPC;
Oral Contraceptive Effect of TVR on OC AUC
Ethinyl estradiol ↓ 28%
Norethindrone ↓ 11%
Additional methods of non-hormonal contraception should be used; ie
hormonal contraceptives may be continued but may not be reliable during
and immediately following TVR dosing
Oral Contraceptive Effect of BOC on OC AUC
Ethinyl estradiol ↓ 24%
Drospirenone 99%
Kassera C et al CROI 2011; Abs 118; Boceprevir EU SmPC.
Enzyme inducing agents reduce telaprevir
and boceprevir exposure: Victim
Telaprevir EU SmPC; van Heeswijk R et al, CROI 2011; Abstract 119.
Co-medication
Effect on telaprevir Effect on boceprevir
AUC AUC
Efavirenz (600 mg qd) 26% 19% (Cmin 44%)
Decrease in Telaprevir exposure substantially offset by increasing
dose to 1125 mg q8h.
The clinical outcome of the observed reduction of boceprevir
concentrations has not been directly assessed
Modified from Kassera C, et al. CROI 2011. Abstract 118 Boceprevir EU SmPC
Telaprevir interaction with Methadone:
a further complication:
During telaprevir co-administration vs methadone alone:
– Total Cmin of R-methadone reduced by 31%
– Free fraction of R-methadone increased by 26%
– No change in the unbound (effective) concentration of R-methadone
Me
dia
n u
nb
ou
nd
R-
me
tha
do
ne
Cm
in (
ng
/mL
)
Methadone Methadone
+ TVR
10
60
110
160
210
10.63 10.45
Methadone Methadone
+ TVR
5
7
9
11
13
15
Me
dia
n f
ree
fra
cti
on
of
R-m
eth
ad
on
e (
%)
Methadone Methadone
+ TVR
5
7
9
11
13
9.98
7.92
260
146
91
To
tal C
min
of
R-
me
tha
do
ne
(n
g/m
L)
van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S491
Protein Binding Displacement
Telaprevir interaction with Buprenorphine
13 HCV negative subjects stable on
buprenorphine/naloxone therapy
TVR had only relatively minor effect on BUP
exposure (Cmax decreased by 20%) or nor-BUP
exposure
No subject experienced withdrawal symptoms
Luo X et al; HEP DART 2011; Abs 132
DAA Clinical Pharmacology
Targeted drug-drug interaction studies are done in
the development programme and some post-
licensing.
Telaprevir and Boceprevir are perpetrators and
victims of DDIs and this gives rise to a degree of
nervousness
Many DDIs can be explained on the basis of
interaction with CYP3A4 but not all.
DAA: direct-acting antiviral; DDI: drug-drug interaction
DAAs and Lipid Lowering Agents
Drug CYP3A4
substrate
CYP3A4
inhibitor Transporter substrate
Atorvastatin X OATP1B1/2B1
Cerivastatin X OATP1B1
Lovastatin X
Simvastatin X
Pravastatin OATP1B1/3,
Rosuvastatin OATP1B1,
Fluvastatin OATP1B1/2B1
Pitavastatin OATP1A2/1B3
Gemfibrozil 2C9
Contraindication or Caution when co-administering telaprevir and statins
with CYP3A4 mediated metabolism……but
Can you avoid using a statin during DAA treatment?
Co-administered drug Dosage
LSM ratio (90% CI), based on AUC
Co-administered drug Telaprevir
Atorvastatin 20 mg* 7.9
(6.8–9.1)
↔
15
16
DAAs and Lipid Lowering Agents
17
Contraindications with telaprevir and
boceprevir
Class Agent Telaprevir1 Boceprevir2
Alpha-1 receptor
antagonists Alfuzosin CI No recommendation
Antiarrhythmics Amiodarone, bepridil, quinidine
CI
(CI with class Ia/III
except IV lidocaine)
Bepridil contraindicated. Caution with
amiodarone/quinidine
Anticonvulsants Carbamazepine, phenobarbital, phenytoin CI No data available: not recommended
Antihistamines Astemizole, terfenadine CI No recommendation
Antimalarials Lumefantrine, halofantrine No recommendation CI
Antimycobacterials Rifampicin CI No data available: not recommended
Antipsychotics Pimozide CI CI
Benzodiazepines Oral midazolam, oral triazolam CI CI
Digestive motility
stimulants Cisapride CI No recommendation
Ergot rye derivatives Dihydroergotamine, ergonovine,
ergotamine, methylergonovine CI CI
Herbal products St. John’s wort (Hypericum perforatum) CI No recommendation
HMG-CoA reductase
inhibitors Atorvastatin, simvastatin, lovastatin CI
No data available. Therapeutic
monitoring recommended (atorvastatin,
simvastatin)
PDE5 inhibitors* Sildenafil, tadalafil CI No recommendation
Tyrosine kinase
inhibitors Not specified No recommendation CI
1. Telaprevir EU SmPC; 2. Boceprevir EU SmPC Italic: removed/not available in all countries; *for pulmonary arterial hypertension
Implications for Clinical Practice
Peg-IFN alfa + ribavirin* Peg-IFN alfa +
ribavirin Telaprevir + PR
0 48 Weeks 4 24 36 12
PR
lead-in BOC + PR
24, 32 or 44 weeks**
12 weeks
PR: peginterferon (Peg-IFN) + ribavirin
*PR must be continued up to Week 48 in patients with cirrhosis, prior partial and null responders and in
treatment-naïve patients or prior relapsers without cirrhosis not achieving undetectable HCV RNA at
Week 4 and 12 (but with HCV RNA <1000 IU/mL at these timepoints)
**In patients receiving 32 weeks of boceprevir, PR alone must be continued up to Week 48 Telaprevir EU SmPC; Boceprevir EU SmPC
HIV-HCV Co-Infection
Interaction of Telaprevir with Boosted HIV
PIs (Healthy volunteer data)
Co-administered drug n
Change in AUC (%)
HIV PI Telaprevir
Lopinavir/r
(LPV/r) 21
Atazanavir/r
(ATV/r) 20 17%* 20%
Darunavir/r
(DRV/r) 20 40% 35%
Fosamprenavir/r
(fAPV/r) 20 43% 32%
LPV/r, DRV/r and fAPV/r not recommended in combination with telaprevir
* Cmin increased by ~ 70%
Mechanistic understanding of observed DDI is inconsistent with CYP3A4
interactions
q8h: every 8 hours
Van Heeswijk R et al CROI 2011; Abs 119; Telaprevir EU SmPC
54%
Interaction of Boceprevir and Boosted HIV PIs
(Healthy volunteer data)
% Change in AUC of
Boosted PI
% Change in AUC of
Boceprevir
Atazanavir/r
Lopinavir/r
Darunavir/r
Hulskotte E et al; CROI 2012 Abs 771LB
35%
34%
44%
45%
32%
Not recommended to coadminister boceprevir and
ritonavir boosted PIs (FDA; Merck)
‘ATV/r can be considered on a case by case basis if
patient has no prior HIV drug resistance’ (EMEA)
Telaprevir & Boceprevir interaction with
NNRTIs:
NNRTI Effect of TVR on
AUC
Effect of NNRTI on
TVR AUC
Etravirine ↓ 16%
Rilpivirine 1.8-fold ↓ 8%
NNRTI Effect of BOC on
AUC
Effect of NNRTI on BOC
AUC
Etravirine ↓ 23% 10%
Rilpivirine ND ND
Based on the PK data - dose adjustment not required.
Based on the PK data - dose adjustment not considered necessary
Kakuda T et al; IWCPHT 2012; Abs 0_18; Hammond K et al, IWCPHT 2012; Abs 0-15
Telaprevir: Summary of DDIs with HIV
antiretrovirals HIV antiretroviral Recommendation
Studies completed
Atazanavir/r Clinical and laboratory monitoring for hyperbilirubinemia is
recommended
Darunavir/r
Fosamprenavir/r
Lopinavir/r Not recommended
Efavirenz TVR dose increase necessary (1125 mg q8h)
Etravirine No dose adjustment required*
Rilpivirine No dose adjustment required*
Raltegravir (non CYP) No dose adjustment required**
Tenofovir Increase in TFV (30%). Clinical and laboratory monitoring is
warranted
Telaprevir EU SmPC
All the PK Interaction studies are in HEALTHY VOLUNTEERS
* Data presented by Kakuda et al at 13th HIV Pharmacology Workshop, Barcelona, April 16-18th 2012; ** van
Heeswijk R et al; ICAAC 2011; Abs A1-1738a
25
Telaprevir in Combination with Pegylated Interferon--2a+RBV in HCV/HIV-co-infected Patients: A 24-Week Treatment Interim Analysis Douglas Dieterich*1, V Soriano2, K Sherman3, P-M Girard4, J Rockstroh5, B Adiwijaya6, S McCallister6, N Adda6, L Mahnke6, M Sulkowski7, on behalf of the Study 110 Team 1Mt Sinai Sch of Med, New York, US; 2Hosp Carlos III, Madrid, Spain; 3Univ of Cincinnati , OH, US; 4Hosp St Antoine, Paris, France; 5Univ of Bonn, Germany; 6Vertex Pharm Inc, Cambridge, MA, US; 7Johns Hopkins Univ Sch Med, Baltimore, MD, US
ATV/r did not cause a decrease in TVR concentrations (cf healthy)
TVR dose increase compensated for EFV effect
ATV concentrations increased in T + P/R group by 18% in keeping
with healthy data.
Boceprevir: Summary of DDIs with HIV
antiretrovirals
HIV antiretroviral Recommendation
Studies completed
Atazanavir/r
Darunavir/r
Lopinavir/r Not recommended
Efavirenz Reduction in boceprevir levels; clinical outcome not directly
assessed
Etravirine No dose adjustment required*
Raltegravir (non CYP) No dose adjustment required**
Tenofovir No change in TFV AUC but Cmax increased by 32%. No
dose adjustment but clinical/laboratory monitoring warranted
All the PK Interaction studies are in HEALTHY VOLUNTEERS
*De Kanter C, et al. CROI 2012. Abstract 772LB; **Hammond K et al, IWCPHT 2012; Abs O-15 Abs Victrlelis SmPC
27
Boceprevir plus Peginterferon /Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results J Mallolas, S Pol, A Rivero, H Fainboim, C Cooper, J Slim, S Thomson, J Wahl, W Geaves, M Sulkowski, Spain, France, Argentina, Canada, USA.
Included patients on ATV/r; LPV/r, DRV/r, Raltegravir.
EASL 2012; Abs 50
8,8 14,7
23,5 32,4 29,4 26,5
4,7
42,2
59,4
73,4 65,6 60,7
0
20
40
60
80
100
4 8 12 24 EOT SVR12
Treatment Week
P/R BOC + P/R
Pe
rce
nt
wit
h V
iro
log
ic
Re
sp
on
se
28
Boceprevir plus Peginterferon /Ribavirin for the Treatment of HCV/HIV-co-infected Patients: End of Treatment (Week-48) Interim Results J Mallolas, S Pol, A Rivero, H Fainboim, C Cooper, J Slim, S Thomson, J Wahl, W Geaves, M Sulkowski, Spain, France, Argentina, Canada, USA.
Included patients on ATV/r; LPV/r, DRV/r, Raltegravir.
3/64 pts on BOC + P/R had HIV breakthrough – not
suggestive of systematic interaction.
SVR12 by HIV Drug
PR (27%) BOC + PR (62.5%)
ATV/r 8/13 (62%) 12/18 (67%)
LPV/r 0/10 (0%) 10/15 (67%)
DRV/r 0/5 (0%) 8/12 (67%)
Other PI/r 0/3 (0%) 4/7 (57%)
Raltegravir 1/3 (33%) 3/7 (43%)
EASL 2012; Abs 50
DAA Clinical Pharmacology
The HCV-HIV interactions (Healthy volunteers) are:
unexpected, inconsistent and difficult to explain.
Need information on pharmacokinetics in HCV patients
– the magnitude of interactions maybe different.
– Interferon may be exerting enough anti HIV activity to
protect against ‘low’ HIV drug concentration.
Perhaps total concentrations reduced but ‘free’
concentrations less affected – need data!
We do have ‘safer’ ARV options until there is clarity.
What about the next generation of
DAAs?
TMC435 (Simeprivir)
Reversible NS3/4A protease
inhibitor
150 mg dose in Phase III
Weak inhibitory effect on CYP3A
suggest less DDI potential
Simmen K et al Int Liver Congress Hong Kong 2008; Abs 507. Beumont-Mauviel M et al AASLD 2011; Abs 1353 & 1354
Methadone No effect of TMC435 on either R- or S-methadone
in subjects stable on methadone therapy.
Escitalopram No effect of TMC435 on escitalopram exposure
TMC435 (Simeprivir) Interactions
Efavirenz TMC435 AUC reduced by 71%. AVOID use.
Rilpivirine No effect of RPV on TMC435 AUC. RPV exposure
increased by 12%. No Dose Adjustment.
Raltegravir TMC435 AUC decreased 11%. RPV exposure not
altered. No Dose Adjustment.
Tenofovir TMC435 AUC decreased 14%. TFV exposure
increased 18%. No Dose Adjustment.
Ouwerkerk-Mahadevan S et al 19th CROI 2012; Abs 49
And...
CYP3A
substrate?
Interaction
Potential
Interaction data
BI 201355 YES Yes Awaited
Daclatasvir YES
Yes
ATV/r increases DCV
EFV decreases DCV
TDF no effect on DCV
Alisporivir YES
Yes Awaited
Danoprevir/r YES
Boosted by
ritonavir - Yes
Awaited
GS-7977 NO Intracellular
phosphorylation
-Less
No effect on
methadone
33
Sane R et al, 46th EASL 2011; Bifano M et al; CROI 2012; Abs 618; Crabbe R et al; Exp Opin Inv Drugs 2009; 18: 211-220;
Denning JM et al AASLD 2011; Abs 372.
Thank you
34