Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and

Drug-Drug Interactions

C Kasserra, E Hughes, M Treitel, S Gupta, and E O'Mara

International Conference on Viral HepatitisApril 11, 2011Baltimore, MA

• Full time employee of Merck and Co. o own stock options

Disclosure Statement

Boceprevir: Background

• Boceprevir (SCH 503034, BOC) o Protease inhibitor of the ketoamide classo Binds reversibly to active site of HCV NS3

protease to inhibit HCV replication (IC90 400 nM)o Phase 3 trials in treatment-naive and treatment-

experienced genotype 1 HCV patients complete highly favourable, statistically significant increases in

SVRo Dose: 800 mg TID with food

• currently in regulatory review

HCV, hepatitis C virus; TID, three times a day.

Boceprevir Absorption, Metabolism, Excretion (1)

• Absorptiono Rapidly absorbed: median Tmax ~2 hrso Less than dose proportional increases in steady state exposureo No accumulationo Food increases exposure ~40% - 60%o P-gp substrate

• Metabolism & Excretiono Extensively metabolized by two distinct pathways

Aldo keto reductase (AKR) CYP3A4/5

o single dose of 14C-radiolabeled BOC metabolized to one primary ketone-reduced metabolite radioactivity in urine & feces accounted for ~ 9% and 79% of dose only 3% and 8% as parent in urine and feces respectively.

Boceprevir Absorption, Metabolism, Excretion (2)

• Metabolism & Excretion (cont’d)o Mean plasma t½ of ~3.4 hourso Primary route of excretion is hepatic/fecal

• Selectivityo Strong reversible CYP3A4 inhibitoro Not a CYP450 isoenzyme inducero Not a P-gp inhibitor

AKR inhibitorsCYP3A4/P-gp inhibCYP3A4 inducerOther

IbuprofenDiflunisal

KetoconazoleRitonavir

Clarithromycin*EfavirenzTenofovir

Peginterferon -2bRibavirin

Co-administeredDrug

Boceprevir As Victim

Drug-Drug Interaction Studies

CYP3A4substrate

Other

MidazolamDrospirenone/

Ethinyl estradiolEfavirenzTenofovir

Peginterferon -2bRibavirin‡

Co-administeredDrug

Boceprevir As Perpetrator

Diflunisal

N = 5 healthy subjects

aModel-based (least squares) geometric mean; ANOVA extracting the effects due to treatment and subject.AUC(T), area under the plasma concentration versus time curve from time 0 dosing interval; BID, two times a day; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; DIF, diflunisal; LS, least squares; TID, three times a day.

0 10862 4

BOC 800 mg TID

DIF 250 mg BID

Days: 12

Treatment LS MeanaRatio Estimate, %

(90% CI)

Effect of DIF (250 mg BID) on BOC (800 mg TID)

Cmax (ng/mL) BOCBOC + DIF

22591936 86 (56–132)

AUC(T) (ng·h/mL) BOCBOC + DIF

68686597 96 (79–117)

Cmin (ng/mL) BOCBOC + DIF

83108 131 (104–165)

Ketoconazole

AUC(tf), area under the plasma concentration versus time curve to the final measurable sampling time; BID, two times a day; BOC, boceprevir; CI, confidence interval; KET, ketoconazole; TID, three times a day.

1 4 6Day:

BOC 400-mg single dose on day 1

KET 400 mg BID days 1–6 + BOC 400-mg single dose on day 4

1 4N = 12 healthy subjects

BOC + KET vs BOCratio estimates (90% CI)

AUC(tf) 231% (200–267)Cmax 141% (100–199)Cmin N/A

800

600

400

200

00 12 24 36 48 60 72

Boceprevir + Ketoconazole Boceprevir

Time (h)

Mean Concentration of Boceprevir

Ritonavir

Day 17

BOC 400 mg TID BOC 400 mg TID* + RTV 100 mg QD

Day 1 Day 6

*BOC stopped at day 15

N = 16 healthy subjects

BOC + RTV (100 mg QD) vs BOCratio estimates (90% CI)

AUC(T) 81% (73–91)Cmax 73% (57–93)Cmin 104% (62–175)

AUC(T), area under the plasma concentration versus time curve from time 0 dosing interval; BID, two time a day; BOC, boceprevir; CI, confidence interval; RTV, ritonavir; TID, three times a day.

800

600

400

200

020 4 6 8 10

Time (h)

BOC (400 mg TID)BOC (400 mg TID) + RTV (100 mg QD)

Boceprevir (ng/mL)

1000

1200

12

Efavirenz

Treatment LS MeanaRatio Estimate, %

(90% CI)Effect of EFV (600 mg QD) on BOC (800 mg TID)Cmax (ng/mL) BOC

BOC + EFV20381871 92 (78–108)

AUC(0-8h) (ng·h/mL) BOCBOC + EFV

69135630 81 (75–89)

Cmin (ng/mL) BOCBOC + EFV

94.452.5 56 (42–74)

Effect of BOC (800 mg TID) on EFV (600 mg QD)Cmax (ng/mL) EFV

EFV + BOC45735077 111 (102–120)

AUC(0-24h) (ng·h/mL) EFVEFV + BOC

7866794655 120 (115–126)

aModel-based (least squares) geometric mean; ANOVA extracting the effects due to treatment and subject.AUC, area under the plasma concentration-time curve; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; Cmin, minimum observed plasma concentration; EFV, efavirenz; LS, least squares; QD, once daily; TID, three times a day.

Days 1–5: BOC 800 mg TIDDay 6: BOC 800 mg single dose

Days 1–10: • EFV 600 mg

QD

Days 11–15: BOC 800 mg TIDDay 16: BOC 800 mg single doseDays 11–16: EFV 600 mg QD

Washout≥7 days

N = 12 healthy volunteers

Midazolam

–1 6 13

BOC 800 mg TID

1 8

MDZ4 mg

MDZ4 mg

MDZ4 mg

MDZ4 mg

N = 12 healthy volunteers

Days

Treatment LS MeanRatio Estimate, %

(90% CI)

Effect of BOC (800 mg TID) on MDZ (4-mg single doses)

Cmax ng/mL

MDZ (day –1)MDZ + BOC (day 6)MDZ (day 8)MDZ (day 13)

9.9627.69.828.94

277 (236–325)

AUC(0-12hr) (ng·h/mL)

MDZ (day –1)MDZ + BOC (day 6)MDZ (day 8)MDZ (day 13)

52.94280.756.1043.83

530 (466–603)

AUC, area under the plasma concentration-time curve; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; MDZ, midazolam; TID, three times a day.

Drospirenone/Ethinyl estradiol

Treatment LS MeanaRatio Estimate, %

(90% CI)Effect of BOC (800 mg TID) on DRSPCmax (ng/mL) OC

OC + BOC46.073.0 157 (146–170)

AUC(0-8h) (ng·h/mL) OCOC + BOC

6551304 199 (187–211)

Effect of BOC (800 mg TID) on EECmax (ng/mL) OC

OC + BOC54.054.0 100 (91–110)

AUC(0-24h) (ng·h/mL) OCOC + BOC

659499 76 (73–79)

Day 1 Day 8 Day 14

Oral contraceptive: DRSP 3 mg/EE 0.02 mg QD

BOC 800 mg TIDN = 16 healthy volunteers

aModel-based (least squares) geometric mean; ANOVA extracting the effects due to treatment and subject.AUC, area under the plasma concentration-time curve; BOC, boceprevir; CI, confidence interval; Cmax, maximum observed plasma concentration; DRSP, drospirenone; EE, ethinylestradiol; LS, least squares; OC, oral contraceptive; QD, once daily; TID, three times a day.

Drug-Drug Interactions:Boceprevir As Victim

† Ratio estimate of boceprevir PK parameters (in combination vs. alone); = ratio estimate <0.8; = ratio estimate ≥0.8 and ≤1.25; = ratio estimate >1.25.* in presence of diflunisal, compared with boceprevir + diflunisal

No Clinically Relevant Effect of Co-administered Drugs on Boceprevir

AKR inhibitorsCYP3A4/P-gp inhibitorsCYP3A4 inducersOther

IbuprofenDiflunisal

KetoconazoleRitonavir

Clarithromycin*EfavirenzTenofovir

Peginterferon -2bRibavirin

Co-administeredDrug

1.04 ↔ 0.96 ↔ 2.31 ↑ 0.81 ↔ 1.21 ↔ 0.81 ↔ 1.08 ↔ 1.00 ↔ ~0.92 ↔

Mean AUC() Ratio†

Drug-Drug Interactions:Boceprevir As Perpetrator

† Ratio estimate of concomitant drug PK parameters (in combination with Boceprevir vs. alone); = ratio estimate <0.8; = ratio estimate ≥0.8 and ≤1.25; = ratio estimate >1.25.

Effect of Boceprevir on Co-administered Drugs is Predictable

CYP3A4 substrates

Other

Midazolam

Drospirenone/Ethinyl estradiol

EfavirenzTenofovir

Peginterferon -2bRibavirin‡

Co-administeredDrug

5.30 ↑1.99 ↑0.76 ↓1.20 ↔1.05 ↔ 0.99 ↔~0.98 ↔

Mean AUC() Ratio†

Phase 3 sub-analyses: similar safety profile when CYP3A4 substrates (eg. benzodiazepines) or inhibitors (eg. azoles) administered with boceprevir

No Correlation of SVR With Plasma PK

Tx-Experienced Tx-Naive Median, Quartiles

Data from RESPOND-2 and SPRINT-2. AUC=area under the concentration-time curve; Cmin=minimum observed plasma concentration; PK=pharmacokinetic; SVR=sustained virologic response.

No SVR (n=29) SVR (n=87) No SVR (n=29) SVR (n=87)

Drug-Drug Interactions: Summary & Conclusions

Unlikely Victim• Metabolized by two pathways

o Clinically relevant AKR inhibitors not knowno Effect of CYP3A4 inhibitors & inducers modesto Drugs affecting other enzymes/transporters unlikely to alter bocepreviro No dose adjustments of boceprevir required

Predictable Perpetrator • Interaction with sensitive CYP3A4 substrate drugs should be expected• Many drugs are CYP3A4 inhibitors

o These interactions are understood and managed appropriatelyo CYP3A4 substrate drugs with toxicities often dose-titrated as standard

practiceo Many drug classes include alternatives that are not CYP3A4 substrateso No interaction with drugs metabolized by other pathways, such as

standard of care (Peginterferon -2b / ribavirin)

Thanks to:• the subjects and their families who participated in

these studies • investigators• Merck colleagues