Slide 1
Current Drugs: Drug-Drug Interactions
David Back University of Liverpool UK
David Back University of Liverpool
May 2013
HCV med
Co-med
Reduced Efficacy
Toxicity
The major effect of DAAs is to increase concentrations of co-meds but they may also decrease AND co-meds can interact with DAA
Clinical Pharmacology of DAAs DRUG CYP450 Non-
CYP450 Transport Proteins
Telaprevir CYP3A4 • Substrate • Inhibitor
• Transported by P-gp
• Inhibits P-gp • Inhibits
OATP1B1
Boceprevir CYP3A4 • Substrate • Inhibitor
AKR substrate
• Transported by P-gp
• Inhibits P-gp • Inhibits
OATP1B1; OCT1/2
Kessara C et al 18th CROI, Abs 118; Garg V et al 18th CROI, Abs 629; Telaprevir SmPC, 2013; Boceprevir SmPC, 2013; Kiser JJ et al Hepatology 2012; 55: 1620-1628; Kunze A et al Biochem Pharmacol 2012; 84: 1096-1102.
Clinical case: patient characteristics at time of treatment
BMI: body mass index; Hb: haemoglobin; HCV: hepatitis C virus; HDL: high-density lipoprotein
54-year-old male Smoker and no alcohol abuse Treatment naïve
Description
Genotype: HCV G1a Fibrosis stage: F3
HCV disease characteristics
BMI: 28 Type 2 diabetes (taking metformin) High cholesterol and cardiovascular risk >20% (taking atorvastatin) – Total
Chol: 1.70 g/L; HDL: 0.42 g/L Hypertension (taking propranolol) Suffering from mild depression (receiving behavioural therapy) Hb level: 14 g/dL
Other medical information
DDIs: patient’s medications
Telaprevir
Atorvastatin
PR
Metformin
Propranolol
Which medications are a concern with telaprevir?
ED: erectile dysfunction http://www.hep-druginteractions.org
Renal excretion – no interaction expected but we are constantly learning about renal transporters
Not anticipated to cause a problem when combined with DAAs
Metabolised by CYP2D6 (major) – no interaction expected
Metformin
Propranolol
Telaprevir increases exposure to statins
AUC: area under curve 1. Telaprevir EU SmPC
2. http://www.hep-druginteractions.org
Other recommendations:1,2
Telaprevir Recommendation
Atorvastatin AUC ↑788% Contra-indicated
Simvastatin Contra-indicated (CYP 3A4 substrate) Pravastatin Rosuvastatin
Potential interaction may require close monitoring or change of dosing
Treatment decision
Because of interactions Atorvastatin was temporarily stopped for
12 weeks after consultation with the cardiologist No changes were made to the
metformin and propranolol prescriptions
Week 2–8 visits: results
Patient health Patient develops an upper
respiratory tract infection (deemed unrelated to treatment) He develops mild rash His depression worsens
(becomes moderate)
Telaprevir + PR
HCV RNA levels
0
2
4
6
0 4 8 12
HCV
RNA
(log 1
0 IU
/mL)
Weeks
Management of the patient’s upper respiratory tract infection
Clarithromycin
CYP 3A inhibitor & substrate Concern about increase in
telaprevir exposure Also concern of increase in
CLA – this may warrant ECG monitoring due to the possible risk of QT prolongation
A 5-day course of azithromycin was chosen due its reduced likelihood of interactions
Azithromycin
Not a CYP 3A inhibitor or substrate Drug interactions unlikely
http://www.hep-druginteractions.org ECG: electrocardiogram
Choose carefully
Management of mild rash: which corticosteroid?
• Not recommended with telaprevir and boceprevir • Prednisone and methylprednisolone are CYP3A substrates;
levels may significantly increase and lead to side effects
Systemic cortico-steroids
• OK to use concomitantly with HCV PIs • Although not expected to cause significant systemic
absorption – be watchful (lessons form HIV)
Topically applied steroids
http://www.hep-druginteractions.org; Cacoub P, et al. J Hepatol 2012;56:455–463
In this patient, a topically applied corticosteroid (betamethasone) was initiated
Interaction is unlikely*
Venlafaxine
Paroxetine Fluoxetine
Antidepressants and telaprevir
Interaction is likely, caution is advised
Sertraline
Trazodone Mirtazapine
http://www.hep-druginteractions.org
Some Antidepressants are metabolized by CYP 3A4
Some Antidepressants metabolized primarily by non CYP 3A4
* Caution – note escitalopram
Week 8: patient has a car accident
The patient has a car accident at week 8 (breaking his leg) The emergency unit requests advice since the patient informed them about his Hep C medication? The internist wants to administer Morphine and iv Midazolam
Interaction with morphine and midazolam
http://www.hep-druginteractions.org; Telaprevir EU SmPC
Based on metabolism and clearance, a clinically significant interaction is unlikely. Morphine
Midazolam IV
Midazolam IV exposure is likely to be increased (respiratory depression and/or prolonged sedation risk)
Co-administration should be done in a setting ensuring clinical monitoring and appropriate medical management
Back home, the patient is prescribed paracetamol
0
2
4
6
0 12 24 36
HC
V R
NA
(log 1
0 IU
/mL)
Weeks
Treatment outcome: summary
Telaprevir + PR PR
SVR12
Rash disappeared; topical steroid stopped
Depression symptoms improved
Morphine and midazolam IV
Betamethasone Fluoxetine Restart statin
HCV med
HIVmed
Reduced Efficacy
Toxicity
In a co-infected patient we now need to manage the interactions between the HCV and HIV medication as well as other co-meds
Co- med
ATV/r DRV/r LPV/r Efavirenz Rilpivirine Etravirine Raltegravir Elvitegravir/cobi Maraviroc NRTIs
Telaprevir Boceprevir Ribavirin Drugs in pipeline
HCV – HIV DDIs: The predictable and the
unpredictable!
Drug TVR effect on AUC (exposure) BOC effect on
AUC (exposure) Cyclosporine A
4.6-fold increase 2.7-fold increase
Midazolam 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 SmPC; Hulskotte EGJ et al HEPDart 2011; Abs 122 and Abs 123; Kessara C et al, CROI 2011, Abs 118; Boceprevir SmPC
Telaprevir & Boceprevir increase exposure to CYP3A substrates: Perpetrator
Vourvahis M et al. IWCPHT 2013 Abs O-17
Effect of Boceprevir and Telaprevir on the PK of Maraviroc – CYP3A4 drug
Slide 20
Conclusions
Maraviroc should be dosed at 150 mg BID when co-administered with either TVR or BOC – consistent with recommendations for potent CYP3A inhibitors. No dose modification for TVR or BOC
(relative to historical data).
Effect of Telaprevir and Boceprevir on the PK of Rilpivirine (CYP3A4)
The effect of the DAA on Rilpivirine PK was < 12% Finding consistent with CYP3A inhibition
Increase in RPV exposure probably not clinically significant
and no dose adjustment recommended.
Rhee EG, et al. CROI 2013; Atlanta, GA. #537; Kakuda T et al; IWCPHT, 2012, Barcelona, #O-18
Parameter TVR on Rilpivirine BOC on Rilpivirine
Cmin, ng/mL ↑ 93% ↑ 51%
Cmax, ng/mL ↑ 49% ↑ 15%
AUC, ng.hr/mL ↑ 78% ↑ 39%
Effect of Boceprevir on Dolutegravir PK DOL metabolised: UGT1A1 (major) & CYP3A4 (minor)
Slide 23
Effect of Telaprevir on Dolutegravir PK
Similar to Raltegravir – AUC is increased by 30%
Interactions of Telaprevir with Boosted HIV PIs (Healthy volunteer data)
Co-administered drug n
LSM ratio (90% CI), based on AUC
HIV PI Telaprevir Lopinavir/r
(LPV/r) 21 1.06 0.46
Atazanavir/r (ATV/r) 20 1.17* 0.8
Darunavir/r (DRV/r) 20 0.6 0.65
Fosamprenavir/r (fAPV/r) 20 0.53 0.68
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
Telaprevir EU SmPC
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)
But remember that ritonavir has inhibited ~95% of CYP3A
activity so TVR and BOC are exerting other effects.
Effect of Ritonavir and Cobicistat (GS-9350) on midazolam (CYP3A4 drug) clearance
RTV and Cobi are potent inhibitors of CYP3A4
What if the interaction between Telaprevir & Boceprevir and
Boosted HIV PIs was similar to the Methadone interaction?
But what if the HCV PI and HIV PI interaction was similar to TVR-Methadone?:
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
Med
ian
unbo
und
R-
met
hado
ne C
min
(ng/
mL)
Methadone Methadone + TVR
10
60
110
160
210
10.63 10.45
Methadone Methadone + TVR
5
7
9
11
13
15 M
edia
n fr
ee fr
actio
n
of R
-met
hado
ne (%
)
Methadone Methadone + TVR
5
7
9
11
13
9.98
7.92
260
146
91
Tota
l Cm
in o
f R-
met
hado
ne (n
g/m
L)
van Heeswijk R, et al. J Hepatol 2011;54(Suppl. 1):S491
Protein Binding Displacement
Effect of Protein Binding on Darunavir PK with and without Telaprevir
Bertelsen K. IWCPHT 2013.
Bertelsen K IWCPHT 2013
Effect of Protein Binding on Telaprevir PK with and without Darunavir/r
Bertelsen K. IWCPHT 2013
What if DDI’s were ‘significantly’ different in HCV patients
compared to healthy volunteers?
Slide 34
Parameter HCV-infected
Albumin ↓*1
α1-acid glycoprotein ↑↓3
Gastric pH ↑4
Cytokines ↑6
CYP450’s expression or function ↓5
Transporter expression or function ?
* Magnitude of effect dependent on stage of liver involvement † Also hemodynamic changes (portal systemic shunting) and renal changes with hepatic impairment
1 Nagao Y & Sata M. Virology Journal 2010; 7: 375; 2 Monga HK et al. Clin Infect Dis 2001;
33: 240-7; 3 Ozeki T et al. Br J Exp Path 1988; 69: 589-95; 4 Nam YJ et al. Korean J Hepatol 2004; 10: 216-22; 5 Frye RF et al. Clinical Pharmacol Ther 2006; 80: 235-45;
6Huang et al Clin Pharmacol Ther 2010; 87: 32-36
Most DDI studies are in Healthy Subjects: Physiological Changes in Patients
Slide 35
Frye RF et al. Clinical Pharmacol Ther 2006; 80: 235-45
Maybe this would lead you to think that a CYP3A drug would automatically be increased in hepatic impairment!
CYP3A4
0
20
40
60
80
100
CP-A (6) CP-B (21) CP-C (21)*
% o
f con
trol
Johnson TN et al. Clinical Pharmacokin 2010; 49: 189-206
CYP enzyme expression with progressive hepatic impairment
CYP3A4
Slide 36 Impact of Hepatic Impairment on
Telaprevir PK
• Reduced Absorption • Increased clearance
due to reduced protein binding
Impact of Hepatic Impairment on Boceprevir PK
Treitel M et al., Clin Pharmacokin 2012; 51: 619-628.
Slide 40
Suggests
• Complex interplay between an individual drug and hepatic function.
• Involves CYP3A4 and probably transporters • Involves protein binding (TVR 59-76%; BOC
75%; Daclatasvir 99%; Asunaprevir 99%) • Clear differences in hepatic impairment on PK
of the DAAs
Need DDI data in target population – healthy volunteers can only be a guide
HIV-HCV Interaction Studies
The HIV-HCV interaction studies to date have mostly been performed in Healthy volunteers: some are unexpected and difficult to explain.
Need information on PK in HCV patients – the magnitude of interactions maybe different – due to difference in enzyme or transporter expression.
Mechanisms such as protein binding displacement may be involved. Need data.
Interferon may be exerting enough anti HIV activity to protect against ‘low’ HIV drug concentration.
What about DDI’s and the next generation of DAA’s?
Management of Hep Drug-Drug Interactions
45
Dianummer 1Dianummer 2Dianummer 3Clinical case:�patient characteristics at time of treatmentDDIs: patient’s medicationsWhich medications are a concern with telaprevir?Telaprevir increases exposure to statinsTreatment decisionWeek 2–8 visits: resultsManagement of the patient’s upper�respiratory tract infectionManagement of mild rash: which corticosteroid?Antidepressants and telaprevirWeek 8: patient has a car accidentInteraction with morphine and midazolam Treatment outcome: summaryDianummer 16HCV – HIV DDIs:� The predictable and the unpredictable!�Dianummer 18Dianummer 19ConclusionsEffect of Telaprevir and Boceprevir on the PK of Rilpivirine (CYP3A4)Dianummer 22Dianummer 23Interactions of Telaprevir with Boosted HIV PIs�(Healthy volunteer data)�Interaction of Boceprevir and Boosted HIV PIs�(Healthy volunteer data)But remember that ritonavir has inhibited ~95% of CYP3A activity so TVR and BOC are exerting other effects.�Dianummer 27What if the interaction between Telaprevir & Boceprevir and Boosted HIV PIs was similar to the Methadone interaction?�But what if the HCV PI and HIV PI interaction was similar to TVR-Methadone?: Dianummer 30Dianummer 31Dianummer 32What if DDI’s were ‘significantly’ different in HCV patients compared to healthy volunteers?�Dianummer 34Dianummer 35Dianummer 36Dianummer 37Dianummer 38Dianummer 39SuggestsHIV-HCV Interaction StudiesWhat about DDI’s and the� next generation of DAA’s?�Management of Hep Drug-Drug InteractionsDianummer 44Dianummer 45