Pharmacokinetic Enhancement with Ritonavir: More Than It...

Pharmacokinetic Enhancement with Ritonavir: More Than It Seems?

Dale Kempf, Barry Bernstein, Daniel Bow, David Beno, William Chiou, Jürgen Delzer, Jinrong Liu, Kennan Marsh, Keith McDaniel, Rajeev Menon, Tim Middleton, Jianwei Shen, Richard Voorman

5th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June 23, 2010

Acknowledgments: Nancy Shulman (Roche), Rob Ralston (Merck/Schering), Enanta Pharmaceuticals

5th International Workshop on Clinical Pharmacology of Hepatitis Therapy23 June 2010

2

PK Boosting of HCV Protease Inhibitors

• PK boosting with ritonavir is a well-accepted strategy for optimizing the efficacy and safety of protease inhibitors in HIV therapy– Increased plasma trough levels contribute to enhanced antiviral

activity– Lower doses (and lower Cmax) may provide better safety

• Ctrough correlated with antiviral activity

• Similar metabolic pathways for HCV and HIV PIs– Primary metabolism via CYP3A– Metabolism inhibited by ritonavir (in vitro CYP3A Ki = 15 nM)


3

0

20

40

60

80

100

120

0 10 20 30

Time (minutes)

% R

emai

ning

(HLM

)

Telaprevir

Inhibition of the Metabolism of Telaprevir and Boceprevir by Ritonavir in Human Liver Microsomes• Similar inhibition in both human and rat

liver microsomes:0 M Ritonavir0.4 M Ritonavir4 M Ritonavir

0

20

40

60

80

100

120

0 10 20 30

Time (minutes)

% R

emai

ning

(HLM

)

Boceprevir

Kempf et al, Antiviral Chem. Chemother., 2007


4

Pharmacokinetic Boosting of Telaprevir and Boceprevir by Co-dosing with Ritonavir in Rats

Telaprevir + Ritonavir

AUC

>8-fold

C8h >50-fold

Telaprevir alone

Hours after Dose

0.01

0.1

1

10

0 2 4 6 8

Plas

ma

Con

cent

ratio

n (m

cg/m

L)

Mean (±SE) Plasma Concentrations in Rats (5 mg/kg oral dose)

Boceprevir + Ritonavir

AUC

20-fold

C8h >100-fold

Boceprevir alone

0.01

0.1

1

10

0 2 4 6 8

Hours after Dose

Kempf et al, Antiviral Chem. Chemother., 2007


5

PK Boosting of HCV Protease Inhibitors with Ritonavir: Some Interesting Questions Since 2006• Does ritonavir boost HCV PIs in humans?

• Can both classes of HCV PIs (ketoamides and acylsulfonamides) be boosted?

• Does ritonavir boosting increase antiviral activity?

• What is the best PK predictor(s) of PD: Cmax , AUC, Cmin ?

• What are the mechanisms of ritonavir PK boosting?

– Inhibition of metabolism– Inhibition of transport

• Does ritonavir boosting change the liver:plasma ratio?

• What is the effect of ritonavir induction?


6

Structures of Danoprevir and Narlaprevir

NO

HN

O

O

HN

OHN

O

HN

SOO

Narlaprevir (SCH900518)

Ketoamide

O

NO

NH

HN

OO

O

O

NH

SO O

O

N

F

Danoprevir (ITMN-191)

Acylsulfonamide


7

PK Boosting of Narlaprevir by Ritonavir in Humans

Poordad et al, AASLD, 2009

Narlaprevir / Ritonavir200/100 mg QD400/100 mg QD100/100 mg BID


8 8

PK Boosting of Danoprevir by Ritonavir in Humans

• Boosting: Cmax

3-fold, AUC

6-fold, C12h

>50-fold

• 100/100 mg BID vs. 900 mg BID: Cmax

23-fold, AUC

16-fold

Med

ian

dano

prev

irco

ncen

trat

ion

(ng/

mL)

100

10

1

0.1

0.01

0.001

Time (hours)4 8 120

Danoprevir 100 mg

Alone

+ RTV 100 mg

0

100

200

300

400

0 4 8 12 16 20 24

Boosted 100/100 mg BIDUnboosted 900 mg BID

Time (hours)

Haznadar et al, EASL, 2010; Gane et al, EASL, 2010


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Antiviral Activity of Narlaprevir/Ritonavir

Poordad et al, AASLD, 2009


10

13

Boosted 200/100 mg QD (n=8)Boosted 100/100 mg BID (n=9)Unboosted 900 mg BID (n=7)1

Boosted 200/100 mg BID (n=8)

Danoprevir/r + SOC regimens provide more robust Danoprevir/r + SOC regimens provide more robust virologic response than unboosted + SOCvirologic response than unboosted + SOC

Day

15

HCV

RN

A


1111

ABT-450: in vitro Antiviral Activity

Replicon EC50 (nM)Genotype 1a Genotype 1b

no human plasma

40% human plasma

no human plasma

40% human plasma

ABT-450 0.9 19 0.3 7

MK-7009 0.75 29 0.9 21

Danoprevir 2.2 40 1.3 18

.

• ABT-450 is a new acylsulfonamide HCV protease inhibitor

• Metabolism of ABT-450 is primarily mediated through CYP3A4


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ABT-450: in vitro Antiviral Activity

Estimated EC50 (40% Human Plasma, nM)*1a-H77 1b-Con1

R155 K D168 E D168 V R155 K A156 T D168V

ABT-450 370 780 4300 220 70 200

MK-7009 5200 1500 >38000 950 680 2000

Danoprevir 1600 1300 >14000 430 500 90

*Estimated EC50 (mutant, 40% HP) = EC50 (mutant, transient replicon) X Fold EC50(stable replicon, 40% HP).


13

Metabolism and PK of ABT-450Intrinsic Clearance (Liver Microsomes, L/mg/min

Rat Dog Human Human w/RTVABT-450 31 50 88


14

Ritonavir Boosting of ABT-450 in HumansEffect of 100 mg RTV:

• ABT-450 t1/2

from ~2.5 to ~ 5 hours

• ABT-450 Cmax

28-fold

• ABT-450 AUC

48-fold

• C24h

nearly 200-fold

• PK boosting allows for higher exposure and QD dosing

Menon et al, Hep DART, 2009

Species ABT-450 Ritonavir t ½ (h) Cmax (g/mL) AUC (g*h/mL)

Dog5 mg/kg –– 1.2 6.3 18.75 mg/kg 5 mg/kg 1.8 22.7 84.8

Human300 mg –– 2.7 0.12 0.39300 mg 100 mg 4.6 3.4 18.5

Time (h)

0 4 8 12 16 20 24 28 32 36 40 44 48

AB

T-45

0 C

once

ntra

tion

(ng/

mL)

0.1

1

10

100

1000

10000300 mg ABT-450300 mg ABT-450 + 100 mg RTV


15

Mean ABT-450 PK Parameters (Day 14 w/RTV)Dose (mg/kg) 50/100 BID 100/100 BID 200/100 QD 300/100 QDCmax (g/mL) 0.07 0.37 1.5 7.3AUC (g.h/mL) 0.41 1.6 5.6 36

AUC/Dose 16.5 31.5 32.5 128

Time (h)

0 4 8 12 16 20 24 28 32 36 40 44 48

AB

T-45

0 C

once

ntra

tion

(ng/

mL)

0.1

1

10

100

1000

10000300 mg ABT-450300 mg ABT-450 + 100 mg RTV

PK Boosting of ABT-450 by RitonavirLopinavir Boosting by Ritonavir

Menon et al, Hep DART, 2009, Bernstein et al, Hep DART, 2009

ABT-450 Boosting by Ritonavir

0.001

0.01

0.1

1

10

0 6 12 18 24 30 36 42 48

Time (h)

Con

cent

ratio

n (

g/m

L)

Est. RTV in vivo Ki

Ritonavir (+ Lopinavir)Lopinavir (+ Ritonavir)Lopinavir alone


16

Boosting of Metabolically Stable Protease Inhibitor (AE-741) by Ritonavir

Plasma Levels after Oral Dosing in Dogs (3 mg/kg)Species Clint *

Human 13.8

Dog 15.1*L/mg/min

Cmax * AUC#

Alone 16.9 54.3

+ RTV 37.0 435*g/mL, #g h/mL, 0.01

0.1

1

10

100

0 4 8 12 16 20 24Time after Dosing (h)

Con

cent

ratio

n (u

g/m

L)

Alone With Ritonavir


17

Potential PK Boosting Through Transporter Inhibition by Ritonavir

Intestinal Epithelia Hepatic Uptake

Biliary Secretion

Giacomini et al, Nature Reviews: Drug Discovery, 2010


18

Ritonavir May Boost ABT-450 via P-gp Inhibition• Efflux ratio (6.3) in Caco-2 cells

indicates active transport of ABT- 450

• Active efflux partially (but not completely) blocked by selective P-gp inhibitor LY335979

ABT-450 Papp (1X10-6 cm/s)No inhibitor + LY335979

A-to-B 10.1 18.6B-to-A 63.8 59.4

Efflux Ratio 6.3 3.2

• Ritonavir has been reported to inhibit P-gp in vitro (IC50 0.2 - 16 M, multiple systems)*– However, little effect on

BBB P-gp transport of SQV in vivo**

• Most likely inhibition in intestine where local concentrations are high

Intestine Hepatocytes

ABT-450 is a P-gp Substrate

*Gutman et al, Mol. Pharm.,1999, Profit et al, AIDS, 1999, **Huisman et al, Mol. Pharm., 2001


19

Ritonavir Does Not Affect the Liver:Plasma Ratio of ABT-450

0 3 6 9 120.1

1

10

100Plasma; 2 mg/kg

Liver; 2 mg/kg + RTVLiver; 2 mg/kgPlasma; 2 mg/kg + RTV

Time (Hours Post Dose)

Plas

ma

or L

iver

Con

c.(

g/m

L or

g/

g)

Mean = 7.0

Mean = 6.7

Plasma and Liver Concentrations in Dogs


20

ABT-450 Ctrough vs. Time

Study Day

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 161

10

100

AB

T-45

0 C

once

ntra

tion

(ng/

mL)

200/100 QD (N=4)

100/100 BID (N=7)50/100 mg BID (N=8) 300/100 mg QD (N=7)

Bernstein et al, Hep DART, 2009


21

Ritonavir Boosting of HCV PIs: Conclusions• As in HIV therapy, PK boosting by ritonavir can be advantageous for

HCV protease inhibitors– Less frequent dosing greater convenience– Increased Ctrough greater virologic response– Decreased Cmax and AUC potential for lower toxicity

• Both classes of HCV protease inhibitors (ketoamide and acylsulfonamide) may be candidates for PK boosting

• The mechanism of PK boosting of HCV PIs appears more complex than simple CYP3A inhibition (more studies needed)– Intestinal transport likely– Biliary transport possible– Hepatic uptake less likely

• HCV PIs may be affected by ritonavir even if they are metabolically stable

• The boosting effect of other CYP3A inhibitors on HCV PIs may be distinct from ritonavir and requires study


22

AcknowledgmentsDrug Metabolism• Daniel Bow• Jinrong Liu• Jianwei Shen• Richard Voorman• William Chiou• Jürgen DelzerPreclinical PK• David Beno• Kennan Marsh

Discovery

• Keith McDaniel

• Tim Middleton

• Enanta Pharmaceuticals

Clinical / PK

• Rajeev Menon

• Barry Bernstein

• Nancy Shulman (Roche)

• Rob Ralston (Merck/Schering)

Pharmacokinetic Enhancement with Ritonavir: More Than It Seems?�PK Boosting of HCV Protease InhibitorsInhibition of the Metabolism of Telaprevir and �Boceprevir by Ritonavir in Human Liver MicrosomesPharmacokinetic Boosting of Telaprevir and �Boceprevir by Co-dosing with Ritonavir in RatsPK Boosting of HCV Protease Inhibitors with Ritonavir: Some Interesting Questions Since 2006Structures of Danoprevir and NarlaprevirPK Boosting of Narlaprevir by Ritonavir in HumansPK Boosting of Danoprevir by Ritonavir in HumansAntiviral Activity of Narlaprevir/RitonavirAntiviral Activity of Danoprevir/RitonavirABT-450: in vitro Antiviral ActivityABT-450: in vitro Antiviral ActivityMetabolism and PK of ABT-450Ritonavir Boosting of ABT-450 in HumansPK Boosting of ABT-450 by RitonavirBoosting of Metabolically Stable Protease Inhibitor (AE-741) by RitonavirPotential PK Boosting Through Transporter Inhibition by RitonavirRitonavir May Boost ABT-450 via P-gp InhibitionRitonavir Does Not Affect the Liver:Plasma Ratio of ABT-450ABT-450 Ctrough vs. TimeRitonavir Boosting of HCV PIs: ConclusionsAcknowledgments

Pharmacokinetic Enhancement with Ritonavir: More Than It...

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