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 Hepatitis

April 11, 2011
Baltimore, MA

Disclosure Statement
Full time employee of Merck and Co.
o

own stock options

Boceprevir: Background
Boceprevir (SCH 503034, BOC)
Protease inhibitor of the ketoamide class
Binds reversibly to active site of HCV NS3
protease to inhibit HCV replication (IC90 400 nM)
o Phase 3 trials in treatment-naive and treatmentexperienced genotype 1 HCV patients complete
o
o

highly favourable, statistically significant increases in

SVR
o

Dose: 800 mg TID with food

currently in regulatory review

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

Boceprevir Absorption, Metabolism,

Excretion (1)
Absorption
o Rapidly absorbed: median Tmax ~2 hrs
o Less than dose proportional increases in steady state exposure
o No accumulation
o Food increases exposure ~40% - 60%
o P-gp substrate
Metabolism & Excretion
o 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 (contd)
Mean plasma t of ~3.4 hours
Primary route of excretion is hepatic/fecal
Selectivity
o Strong reversible CYP3A4 inhibitor
o Not a CYP450 isoenzyme inducer
o Not a P-gp inhibitor
o
o

Drug-Drug Interaction Studies

Boceprevir As Victim

Co-administered
Drug
AKR inhibitors
CYP3A4/P-gp inhib
CYP3A4 inducer
Other

Ibuprofen
Diflunisal
Ketoconazole
Ritonavir
Clarithromycin*
Efavirenz
Tenofovir
Peginterferon -2b
Ribavirin

Boceprevir As Perpetrator
Co-administered
Drug
CYP3A4

Midazolam
substrate Drospirenone/
Ethinyl estradiol
Other
Efavirenz
Tenofovir
Peginterferon -2b
Ribavirin

Diflunisal
DIF 250 mg BID
BOC 800 mg TID
N = 5 healthy subjects

Days: 0

Treatment

LS

Meana

10

12

Ratio Estimate, %
(90% CI)

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

Cmax (ng/mL)

BOC
BOC + DIF

2259
1936

86 (56132)

AUC(T) (ngh/mL)

BOC
BOC + DIF

6868
6597

96 (79117)

Cmin (ng/mL)

BOC
BOC + DIF

83
108

131 (104165)

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.

Ketoconazole
BOC 400-mg single
dose on day 1

Day: 1

KET 400 mg BID days 16 +

BOC 400-mg single dose on day 4

N = 12 healthy subjects

Boceprevir + Ketoconazole
Boceprevir

800

600

BOC + KET vs BOC

ratio estimates (90% CI)

Mean Concentration
400
of Boceprevir

AUC(tf) 231% (200267)

Cmax 141% (100199)
Cmin N/A

200

0
0

12

24

36

48

60

72

Time (h)
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.

Ritonavir
BOC 400 mg TID

Day 1

BOC 400 mg TID* + RTV 100 mg QD

*BOC stopped at day

15

Day 6

Day 17

N = 16 healthy subjects

1200

BOC (400 mg TID)

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

1000

BOC + RTV (100 mg QD) vs BOC

ratio estimates (90% CI)
AUC(T) 81% (7391)
Cmax 73% (5793)
Cmin 104% (62175)

800

Boceprevir (ng/mL)
600
400
200
0
0

10

12

Time (h)
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.

Efavirenz
Days 15: BOC 800 mg TID
Day 6: BOC 800 mg single dose

Washout
7 days

N = 12 healthy volunteers

Days 110:
EFV 600 mg
QD

Treatment

LS

Days 1115: BOC 800 mg TID

Day 16: BOC 800 mg single dose
Days 1116: EFV 600 mg QD

Meana

Ratio Estimate, %
(90% CI)

Effect of EFV (600 mg QD) on BOC (800 mg TID)

Cmax (ng/mL)

BOC
BOC + EFV

2038
1871

92 (78108)

AUC(0-8h) (ngh/mL)

BOC
BOC + EFV

6913
5630

81 (7589)

Cmin (ng/mL)

BOC
BOC + EFV

94.4
52.5

56 (4274)

Effect of BOC (800 mg TID) on EFV (600 mg QD)

Cmax (ng/mL)

EFV
EFV + BOC

4573
5077

111 (102120)

AUC(0-24h) (ngh/mL)

EFV
EFV + BOC

78667
94655

120 (115126)

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.

Midazolam
MDZ
4 mg

MDZ
4 mg

MDZ
4 mg

MDZ
4 mg

BOC 800 mg TID

1 1

Days

13

N = 12 healthy volunteers

Treatment

LS Mean

Ratio Estimate, %
(90% CI)

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

Cmax ng/mL

AUC(0-12hr) (ngh/mL)

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

9.96
27.6
9.82
8.94

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

52.94
280.7
56.10
43.83

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.

277 (236325)

530 (466603)

Drospirenone/Ethinyl estradiol
N = 16 healthy volunteers

BOC 800 mg TID

Oral contraceptive: DRSP 3 mg/EE 0.02 mg QD

Day 1

Day 8

Treatment

Day 14

LS

Meana

Ratio Estimate, %
(90% CI)

Effect of BOC (800 mg TID) on DRSP

Cmax (ng/mL)

OC
OC + BOC

46.0
73.0

157 (146170)

AUC(0-8h) (ngh/mL)

OC
OC + BOC

655
1304

199 (187211)

Effect of BOC (800 mg TID) on EE

Cmax (ng/mL)

OC
OC + BOC

54.0
54.0

100 (91110)

AUC(0-24h) (ngh/mL)

OC
OC + BOC

659
499

76 (7379)

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
No Clinically Relevant Effect of
Co-administered Drugs on Boceprevir

AKR inhibitors
CYP3A4/P-gp inhibitors
CYP3A4 inducers
Other

Co-administered
Drug

Mean AUC( ) Ratio

Ibuprofen
Diflunisal
Ketoconazole
Ritonavir
Clarithromycin*
Efavirenz
Tenofovir
Peginterferon -2b
Ribavirin

1.04
0.96
2.31
0.81
1.21
0.81
1.08
1.00
~0.92

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

Drug-Drug Interactions:
Boceprevir As Perpetrator
Effect of Boceprevir on Co-administered
Drugs is Predictable
Co-administered
Drug
CYP3A4 substrates

Other

Midazolam
Drospirenone/
Ethinyl estradiol
Efavirenz
Tenofovir
Peginterferon -2b
Ribavirin

Mean AUC( ) Ratio

5.30
1.99
0.76
1.20
1.05
0.99
~0.98

Phase 3 sub-analyses: similar safety profile when CYP3A4 substrates (eg.

benzodiazepines) or inhibitors (eg. azoles) administered with boceprevir

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.

No Correlation of SVR With Plasma PK

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

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

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.

Drug-Drug Interactions:
Summary & Conclusions
Unlikely Victim
Metabolized by two pathways
o Clinically relevant AKR inhibitors not known
o Effect of CYP3A4 inhibitors & inducers modest
o Drugs affecting other enzymes/transporters unlikely to alter boceprevir
o 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 appropriately
o CYP3A4 substrate drugs with toxicities often dose-titrated as standard
practice
o Many drug classes include alternatives that are not CYP3A4 substrates
o 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