Clinical Pharmacology of Boceprevir (BOC)

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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 (cont’d)
Mean plasma t½ 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
2
4
Treatment
8
6
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 (56–132)
AUC(T) (ng·h/mL)
BOC
BOC + DIF
6868
6597
96 (79–117)
Cmin (ng/mL)
BOC
BOC + DIF
83
108
131 (104–165)
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 1–6 +
BOC 400-mg single dose on day 4
4
1
4
6
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% (200–267)
Cmax 141% (100–199)
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% (73–91)
Cmax 73% (57–93)
Cmin 104% (62–175)
800
Boceprevir (ng/mL)
600
400
200
0
0
2
4
6
8
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 1–5: BOC 800 mg TID
Day 6: BOC 800 mg single dose
Washout
≥7 days
N = 12 healthy volunteers
Days 1–10:
• EFV 600 mg
QD
Treatment
LS
Days 11–15: BOC 800 mg TID
Day 16: BOC 800 mg single dose
Days 11–16: 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 (78–108)
AUC(0-8h) (ng·h/mL)
BOC
BOC + EFV
6913
5630
81 (75–89)
Cmin (ng/mL)
BOC
BOC + EFV
94.4
52.5
56 (42–74)
Effect of BOC (800 mg TID) on EFV (600 mg QD)
Cmax (ng/mL)
EFV
EFV + BOC
4573
5077
111 (102–120)
AUC(0-24h) (ng·h/mL)
EFV
EFV + BOC
78667
94655
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.
Midazolam
MDZ
4 mg
MDZ
4 mg
MDZ
4 mg
MDZ
4 mg
BOC 800 mg TID
–1 1
Days
6
13
8
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) (ng·h/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 (236–325)
530 (466–603)
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 (146–170)
AUC(0-8h) (ng·h/mL)
OC
OC + BOC
655
1304
199 (187–211)
Effect of BOC (800 mg TID) on EE
Cmax (ng/mL)
OC
OC + BOC
54.0
54.0
100 (91–110)
AUC(0-24h) (ng·h/mL)
OC
OC + BOC
659
499
76 (73–79)
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
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