Pharmacodynamics and Drug-Drug

Interactions in HCV/HIV Co-Infected

Persons on Treatment with DAAs

Courtney V. Fletcher, Pharm.D.

Dean, College of Pharmacy

Professor, Department of Pharmacy Practice and Division of

Infectious Diseases

University of Nebraska Medical Center

Pharmacokinetics and Pharmacodynamics

- Lessons Learned from HIV -

Pharmacokinetics matter,

Pharmacodynamics (drug concentrations) matter,

Resistance matters,

Adherence matters, and

Convenience and tolerability matters.

Predictive Value of EFV Concentrations for

Viral Suppression and CNS Adverse Effects

Viral

suppression

CNS

adverse

effects

Optimal range

Plasma Efavirenz (ng/mL)

10000 1000 100

0

60

80

100

40

20

Pro

babili

ty (

%)

Marzolini C, et al. AIDS 2001;15:71-75.

Boceprevir Exposure-Response

Relationships

Pro

bab

ilit

y o

f S

VR

Pro

bab

ilit

y o

f A

nem

ia

Wenning L, Flexner C, et al. AASLD 2012, Abstract 770.

Hemoglobin Decline and SVR with BOC/PR

0

10

20

30

40

50

60

70

80

≤ 1 >1-2 >2-3 >3-4 >4-5 >5

% S

VR

Maximum Hemoglobin Decline During Treatment (g/dL)

Sulkowski M, et al. Hepatology 2013;57:974-9

Telaprevir Exposure Response

Relationships

FDA. Telaprevir NDA Briefing Document.

TVR AUC24 at 750 q8h = 66,900 ± 26,100 ng*h/mL

Telaprevir PK Parameters from

q8h and q12h Dosing

Parameter Q8h (IFN alfa 2a) N=6 Q12h (IFN alfa 2a) N=10

Cmin (ng/mL) 2624 ± 507 2134 ± 620

Cmax (ng/mL) 4523 ± 786 4882 ± 784

AUC (ng*h/mL) 85,890 ± 17,610 81,670 ± 20,090

Marcellin P, et al. Gastroenterology 2011; 40:459-468

Probability of Achieving HIV-RNA < 50cpm

as a Function of RAL Trough Conc.*

Rizk ML, et al. Antimicrob Agents Chemother 2012;56:3101-6.

* 800 mg QD arm; stratified by log baseline HIV RNA

Raltegravir Once vs. Twice Daily

Eron JJ, et al. Lancet Infect Dis 2011;11:907-15

clinicaloptions.com/hepatitis

Highlights of AASLD 2012

SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups

Similar safety and tolerability profile in both treatment arms

OPTIMIZE: Efficacy of Telaprevir BID vs

Telaprevir q8h in GT1 HCV Infection

Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.

TVR q8h/PR

TVR BID/PR

SV

R1

2 (

%)

0

20

40

60

80

100

CC CT TT

n/ N =

87 92

68 68 65 66

92/ 106

97/ 105

141/ 208

139/ 206

37/ 57

38/ 58

F0-2 F3/4

78 81

59 58

209/ 268

213/ 264

61/ 103

61/ 105

IL28B GT Liver Disease Status

BOC and TVR – Pharmacodynamic

Interpretations

Within the range of concentrations observed at FDA-

approved doses, only weak relationships were observed

with SVR.

These data suggest usual doses achieve concentrations

on the plateau of the exposure SVR-response curve.

This suggestion is strengthened for TVR with an

equivalent response observed with q8h vs q12h (higher

Cmax, lower Cmin) dosing.

Higher BOC and TVR exposures were associated with

an increased risk of anemia.

Intrinsic or extrinsic (e.g. DDIs) that affect BOC or TVR

concentrations have the potential to affect HCV

response or toxicity.

Do Drug Interactions Matter?

HAART, Antiepileptics and HIV Response

US Military HIV Natural History Study cohort

Use of PI or NNRTI-based regimen for ≥ 6 months

AED drug use for ≥ 28 consecutive days during HAART

AEDs grouped as CYP inducers (phenytoin, carbamazepine, or

phenobarbital) or other (lamotrigine, levetiracetam, gabapentin).

Concurrent enzyme inducing AEDs increased the risk of

virologic failure and should be avoided.

Outcome EI AED (N=19)

Other AED (N=85)

Odds Ratio

Virologic Failure 62.5% 26.7% 4.58

VL < 400 cpm at 6 mos. 33.3% 71.4% 0.20

VL < 400 cpm at 12 mos. 36.4% 75.0% 0.19

Okulicz J, et al. AIDS Res Ther 2011;8:18.

Drug-Drug Interactions: Management

Concepts

Some interactions are useful

Some interactions can be managed clinically

Some interactions are profound, and concomitant

administration is contraindicated

Some interactions affect both efficacy and toxicity

Some interactions have unclear clinical significance

BOC and TVR Pharmacology

BOC TVR

Metabolic Pathways AKR1C2 + 1C3, CYP3A CYP3A

Transporter Pathways Substrate for P-gp,

BCRP

Substrate for P-gp

In vitro CYP Inhibition CYP3A

not CYP1A2, 2A6, 2B6,

2C8, 2C9, 2C19, 2D6 or

2E1

CYP3A

not CYP1A2, 2C9, 2C19

or 2D6

In vitro CYP Induction Does not induce

CYP1A2, 2B6, 2C8,

2C9, 2C19 or 3A

Low potential to induce

CYP2C, 3A or 1A

In vitro Transporter

Inhibition Effects

P-gp (weak),

OATP1B1 & 1B3

P-gp, OCT1 & 2, MATE1

OATP1B1 & 1B3

In vitro Transporter

Induction Effects

?

(no validated in vitro system)

Protein Binding 68-75% 59-76%

BOC and TVR Clinical Pharmacology

BOC TVR

Evidence for CYP Substrate

Inhibition by ketoconazole

Induction by efavirenz

+ (AUC ratio 2.31)

+ (AUC ratio 0.81)

+ (AUC ratio 1.62)

+ (AUC ratio 0.74)

Evidence for CYP Inhibition

Inhibition of midazolam

Inhibition of atorvastatin

Inhibition of tacrolimus

+ (AUC ratio 5.3)

+ (AUC ratio 2.3)

+ (AUC ratio 17.1)

+ (AUC ratio 9.0)

+ (AUC ratio 7.9)

+ (AUC ratio 70.3)

Evidence for P-gp Inhibition

Inhibition of digoxin

Inhibition of raltegravir

Inhibition of TDF

NA

+ (AUC ratio 1.04)

+ (AUC ratio 1.05)

+ (AUC ratio 1.85)

+ (AUC ratio 1.31)

+ (AUC ratio 1.30)

Evidence for P-gp Induction ? ?

Evidence for Protein Binding

Displacement

? + (R-methadone)

Effect of RTV-Boosted PIs on BOC and

TVR

-18 -15

-35 -32

-57 -52

-60

-50

-40

-30

-20

-10

0

10

20

% C

han

ge in

BO

C o

r TV

R C

min

ATV/RTV DRV/RTV LPV/RTV

Boceprevir Telaprevir

Effect of BOC and TVR on the RTV-Boosted

PIs, ATV, LPV and DRV

-49 -59 -43

85

-42

14

-80

-60

-40

-20

0

20

40

60

80

100

% C

han

ge in

PI C

min

BOC TVR

ATV/RTV DRV/RTV LPV/RTV

Effect of Tipranavir on RTV-boosted

Atazanavir, Amprenavir and Saquinavir

Walmsley S at al. JAIDS 2008;47:429-40.

Effect of Telaprevir on Methadone

TVR (60-76%) and methadone (85%) are bound to plasma proteins,

mainly AAG and albumin.

TVR reduced R-methadone total concentrations by ≈ 30%.

Unbound R-methadone, primarily responsible for opioid effect, was

unchanged: mean Cmin 10.63 ng/mL alone and 10.45 ng/mL with TVR.

No withdrawal symptoms were observed; no dose adjustment is

necessary when initiating TVR; close monitoring still recommended.

van Heeswijk R, et al. EASL 2011. Abstract 654.

BOC and TVR with Etravirine and Rilpivirine

Combination Effect and Recommendation

BOC + ETR 1 ETR: AUC and Cmin ≈ 25%

BOC: AUC 10%; Cmin 12%

Rec: Combination not recommended

TVR + ETR 2 ETR: AUC and Cmin ≈ 6%

TVR: AUC 16%; Cmin 25%

Rec: Insufficient data for dose recommendation

(FDA, Feb 27); avoid coadministration at this time.

BOC + RPV 3 RPV: AUC 39%; Cmin 51%

BOC: AUC 6%; Cmin 4%

Rec: Coadministration should be OK (CVF).

TVR + RPV 2 RPV: AUC 78%; Cmin 93%

TVR: AUC 5%; Cmin 11%

Rec: Potential for RPV-associated QTc prolongation;

insufficient data for recommendation; avoid

coadministration at this time (CVF).

1. Hammond K, et al. JAIDS 2013;62:67-73. 2. Kakuda TN, et al. 13th International HIV Clinical Pharmacology

Workshop. Barcelona, Spain, April 2012. Abstract O-18. 3. Rhee E, et al. CROI 2013. Abstract 537.

Plasma and Intracellular Interactions with

Ribavirin (RBV)

Combination Effect and Recommendation

Abacavir and RBV 1 • Plasma RBV concentrations no different when RBV given alone or with ABC. • Intracellular RBV-triphosphate concentrations also not different. • No evidence for an interaction between ABC and RBV.

Telaprevir and RBV 2 • Dose adjusted RBV plasma concentrations were 1.54 higher in HCV-infected persons receiving TPV + PR vs PR only. • Intracellular RBV-MP, DP and TP concentrations in PBMCs were 2.5, 3 and 2-fold higher in TVR + PR vs. PR only. • Increased plasma and intracellular RBV exposure may contribute to the increased rates of anemia seen with TVR and RBV-containing HCV therapy.

1. Andrade A, et al. CROI 2013. Abstract 538. 2. Hammond K, et al. CROI 2013. Abstract 34.

Some Interesting Interaction Data from

AASLD 2012

Combination Effect and Recommendation

TVR and levothyroxine 1 4 patients treated with levothyroxine had increased

TSH after the start of TVR, which returned to

normal after TVR stopped. Mechanism uncertain;

more data needed; monitor.

BOC and ethinyl estradiol

norethindrone 2

AUC and Cmax of EE decreased 26% and 21%,

respectively. Cmax of NE decreased 17%. As long

as at least 1 mg of NE, interaction unlikely to be

clinically significant (FDA label 02/15/13).

BOC or TVR with CSA or

TAC 3,4,5,6,7

5 abstracts describing CSA and TAC dosing in

presence of BOC or TVR. CSA dose reductions

were from 0.5 to 1.5-fold reduction with BOC, and

up to 2.8-fold with TVR. TAC dose reductions were

6-fold for BOC and 25 to 40-fold with TVR.

Collectively provides evidence these interactions

may be manageable with close monitoring.

1. Abstract 1845. 2. Abstract 1901. 3-7. Abstracts 9, 10, 208, 209, 720.

AASLD Annual Meeting, Nov 2012. Boston.

The Future of HIV and HCV Drug-Drug

Interactions

Combination Effect

Sofosbuvir and CSA or TAC 1 CSA, 2% decrease in AUC.

TAC, 9% increase in AUC.

• No clinically relevant interaction.

Sofosbuvir and TDF/FTC/EFV,

RPV, DRV/RTV and RAL 2

HIV: TFV Cmax increased 25%; RAL AUC

decreased 27%.

SOF: Cmax decreased 20% with

TDF/FTC/EFV; RPV, DRV/RTV, RAL

increased AUC 21-45% but no effect on

major metabolite (GS-331007).

• No evidence for clinically relevant

interactions.

Sofusbuvir + ledipasvir + RBV 3 • Well tolerated and achieved potent antiviral

suppression, with a 100% SVR-12 in

treatment-naïve (25/25) and experienced

(9/9) HCV GT1 persons.

1. Abstract 1869; 2. Abstract 1877. AASLD, Nov 2012. Boston. 3. Abstract 41LB,

CROI 2013. Atlanta.

TVR Dynamics – Where Does the Risk of

Virologic Failure Increase?

EFV reduces TVR conc; AUC

decrease is 26%.

With EFV, expected AUC24 is

34,570 ± 11,062 ng*h/mL,

which is an exposure range less

than achieved with TVR usual

dose.

An increased dose of TVR to

1125 mg q8h is recommended

to manage this drug interaction.

Parameter TVR (750 q8h + EFV)

Cmax (ng/mL) 2297 ± 627 (9%)

Cmin (ng/mL) 745 ± 352 (47%)

AUC8 (ng*h/mL) 11,523 ± 3663 (26%)

TFV PK with EFV AUC24 of 34,500. Where

is the inflection point off

the plateau phase?

clinicaloptions.com/hepatitis

Highlights of AASLD 2012

Study 110: SVR24 With TVR + PegIFN/RBV

in HCV GT1/HIV-Coinfected Patients Higher SVR24 rate with TVR-based

therapy TVR plasma levels similar in

patients with or without ART

TVR dose increased to 1125 q8h if given with EFV

– EFV and ATV/RTV plasma levels similar in patients with or without TVR

No HIV breakthroughs in patients using ART during HCV treatment

Safety and tolerability similar to treatment in patients with HCV monoinfection

Sulkowski MS, et al. AASLD 2012. Abstract 54. Reproduced with permission.

Telaprevir + PR

Placebo + PR

74 71 69

80

45

33

50 50

0

20

40

60

80

100

28/ 38

10/ 22

5/ 7

2/ 6

11/ 16

4/ 8

12/ 15

4/ 8

SV

R2

4 (

%)

n/N =

Clinical Significance of Drug-Drug

Interactions

The clinical significance of a drug-drug interaction can

only be determined or confirmed through a clinical study.

In the absence of (or pending) clinical trial data, well

defined exposure-response data provide a basis to

predict the significance of a drug-drug interaction;

however, there will be settings where the existing data

are not informative as to PK and PD of the interaction.

Exercise a measure of caution in managing drug

interactions where no confirmatory clinical data exist.

Drug Interaction Resources

hivinsite.ucsf.edu Updated drug interaction database with references and interactive tool to assess drug interactions.

www.aidsinfo.nih.gov DHHS Guidelines for use of antiretroviral agents and updated drug interaction tables.

www.hiv-druginteractions.org www.hep-druginteractions.org Downloadable drug interaction charts; interactive tools to assess interactions; updated news on published abstracts and papers

www.hivmedicationguide.com Interactive drug interaction database

Micromedex: comprehensive drug database (subscription required); an app is available

Thank You

EXTRAs

Clinical Pharmacology

Major goals in clinical pharmacology are to describe,

quantitate and predict drug effects in humans.

Pharmacokinetics: the time course of a drug in humans

Pharmacodynamics: relationships between the dose or

concentration of drug in the body (exposure) and

measured effects

Pharmacogenetics: relationships among discrete

inherited traits related to drug absorption and disposition,

and response

Drug Interactions

Occur when either the pharmacokinetics or the

pharmacodynamics of one drug is altered by another

are a source of variability in drug response

are graded responses, that are dependent upon the

concentration of the interacting species, and on dose

and time

pharmacokinetic interactions may affect absorption

rate, availability, distribution, and hepatic or renal

clearance

pharmacodynamic interactions may be antagonistic,

synergistic, or additive

Effect of RTV-Boosted PIs on

Boceprevir, Telaprevir and Tenofovir

-18 -15

22

-35 -32

37

-57 -52

51

-60

-40

-20

0

20

40

60

% C

han

ge in

BO

C, T

VR

or

TDF

Cm

in

ATV/RTV DRV/RTV LPV/RTV

Boceprevir Telaprevir Tenofovir