Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions

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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

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Disclosure Statement

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

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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)
• Phase 3 trials in treatment-naive and
  treatment-experienced genotype 1 HCV patients
  complete
• highly favourable, statistically significant
  increases in SVR
• Dose 800 mg TID with food
• currently in regulatory review

HCV, hepatitis C virus TID, three times a day.
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Boceprevir Absorption, Metabolism, Excretion (1)

• Absorption
• Rapidly absorbed median Tmax 2 hrs
• Less than dose proportional increases in steady
  state exposure
• No accumulation
• Food increases exposure 40 - 60
• P-gp substrate
• Metabolism Excretion
• Extensively metabolized by two distinct pathways
• Aldo keto reductase (AKR)
• CYP3A4/5
• 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.

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Boceprevir Absorption, Metabolism, Excretion (2)

• Metabolism Excretion (contd)
• Mean plasma t½ of 3.4 hours
• Primary route of excretion is hepatic/fecal
• Selectivity
• Strong reversible CYP3A4 inhibitor
• Not a CYP450 isoenzyme inducer
• Not a P-gp inhibitor

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Drug-Drug Interaction Studies
Boceprevir As Victim
Boceprevir As Perpetrator
Co-administeredDrug
Co-administeredDrug
CYP3A4 substrate Other
Midazolam Drospirenone/Ethinyl
estradiol Efavirenz TenofovirPeginterferon
?-2b Ribavirin
AKR inhibitors CYP3A4/P-gp inhib CYP3A4
inducer Other
IbuprofenDiflunisal KetoconazoleRitonavirClarit
hromycin Efavirenz TenofovirPeginterferon
?-2bRibavirin
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Diflunisal
DIF 250 mg BID
BOC 800 mg TID
0
10
8
2
4
Days
12
6
N 5 healthy subjects
Treatment
LS Meana
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.
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Ketoconazole
BOC 400-mg single dose on day 1
KET 400 mg BID days 16 BOC 400-mg single dose
on day 4
Day
1
4
1
4
6
N 12 healthy subjects
Boceprevir Ketoconazole Boceprevir
800
600
BOC KET vs BOC ratio estimates (90
CI) AUC(tf) 231 (200267) Cmax 141
(100199) Cmin N/A
Mean Concentration of Boceprevir
400
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.
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Ritonavir
BOC 400 mg TID RTV 100 mg QD
BOC 400 mg TID
BOC stopped at day 15
Day 1
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
2
0
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.
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Efavirenz

• Days 110
• EFV 600 mg QD

Days 1115 BOC 800 mg TID Day 16 BOC 800 mg
single dose Days 1116 EFV 600 mg QD
Days 15 BOC 800 mg TID Day 6 BOC 800 mg single
dose
Washout 7 days
N 12 healthy volunteers
Treatment
LS 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.
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Midazolam
MDZ 4 mg
MDZ 4 mg
MDZ 4 mg
MDZ 4 mg
BOC 800 mg TID
1
6
1
13
8
Days
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
MDZ (day 1) MDZ BOC (day 6) MDZ (day 8) MDZ
(day 13)
9.96 27.6 9.82 8.94
277 (236325)
AUC(0-12hr) (ngh/mL)
MDZ (day 1) MDZ BOC (day 6) MDZ (day 8) MDZ
(day 13)
52.94 280.7 56.10 43.83
530 (466603)
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.
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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
Day 14
Treatment
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.
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Drug-Drug InteractionsBoceprevir As Victim
No Clinically Relevant Effect of Co-administered
Drugs on Boceprevir
Co-administeredDrug
Mean AUC(?) Ratio
IbuprofenDiflunisal KetoconazoleRitonavirClarit
hromycin Efavirenz TenofovirPeginterferon
?-2bRibavirin
1.04 ? 0.96 ? 2.31 ? 0.81 ? 1.21 ? 0.81 ?
1.08 ? 1.00 ? 0.92 ?
AKR inhibitors CYP3A4/P-gp inhibitors CYP3A4
inducers Other
Ratio estimate of boceprevir PK parameters (in
combination vs. alone) ? ratio estimate lt0.8
? ratio estimate 0.8 and 1.25 ? ratio
estimate gt1.25. in presence of diflunisal,
compared with boceprevir diflunisal
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Drug-Drug InteractionsBoceprevir As Perpetrator
Effect of Boceprevir on Co-administered Drugs is
Predictable
Co-administeredDrug
Mean AUC(?) Ratio
CYP3A4 substratesOther
MidazolamDrospirenone/Ethinyl
estradiol EfavirenzTenofovirPeginterferon
?-2bRibavirin
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 lt0.8 ? ratio
estimate 0.8 and 1.25 ? ratio estimate gt1.25.
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No Correlation of SVR With Plasma PK
No SVR (n29) SVR (n87)
No SVR (n29) SVR (n87)
Tx-Experienced
Tx-Naive
Median, Quartiles
Data from RESPOND-2 and SPRINT-2. AUCarea under
the concentration-time curve Cminminimum
observed plasma concentration PKpharmacokinetic
SVRsustained virologic response.
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Drug-Drug Interactions Summary Conclusions

• Unlikely Victim
• Metabolized by two pathways
• Clinically relevant AKR inhibitors not known
• Effect of CYP3A4 inhibitors inducers modest
• Drugs affecting other enzymes/transporters
  unlikely to alter boceprevir
• No dose adjustments of boceprevir required
• Predictable Perpetrator
• Interaction with sensitive CYP3A4 substrate drugs
  should be expected
• Many drugs are CYP3A4 inhibitors
• These interactions are understood and managed
  appropriately
• CYP3A4 substrate drugs with toxicities often
  dose-titrated as standard practice
• Many drug classes include alternatives that are
  not CYP3A4 substrates
• No interaction with drugs metabolized by other
  pathways, such as standard of care (Peginterferon
  ?-2b / ribavirin)

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• Thanks to
• the subjects and their families who participated
  in these studies
• investigators
• Merck colleagues