Pharmacokinetic Interaction Between the
HCV Protease Inhibitor Boceprevir and
Digoxin in Healthy Adult Volunteers
Patricia Jumes,1 Hwa-Ping Feng,1 Fengjuan Xuan,1 Stephen Youngberg,2
John Wagner,1 Joan Butterton1
1Merck
Sharp & Dohme Corp, Whitehouse Station, NJ, USA;
2Celerion, Lincoln, NE, USA
Background
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Boceprevir is a potent, orally administered ketoamide inhibitor
targeting the active site of the HCV NS3 protease1-3
Boceprevir is metabolized by aldo-keto reductase and
cytochrome P450 3A44
In vitro studies provide conflicting data about whether
boceprevir is an inhibitor of the efflux transporter P-gp
– Initial data from efflux studies using Caco-2 cells
suggested that boceprevir is a P-gp substrate as well as
a P-gp inhibitor (inhibition of digoxin efflux 50 ~25 µM)
• However, Caco-2 cells express multiple transporters
• Studies repeated using bidirectional transport studies in LLC-PK1 cells
and LLC-PK1 cells stably expressing human MDR1 P-gp cDNA (LLCMDR1 cells)
– LLC-PK1–derived cell lines can form a tight monolayer and more
accurately assess vectorial transport of test articles from
basolateral to apical and vice versa
HCV, hepatitis C virus; NS3, nonstructural protein 3; P-gp, P-glycoprotein.
1. Malcolm BA, et al. Antimicrob Agents Chemother. 2006;50:1013-20; 2. Bacon B, et al. N Engl J Med. 2011;364:1207-17;
3. Poordad F, et al. N Engl J Med. 2011;364:1195-206; 4. Ghosal A, et al. Drug Metab Dispos. 2011;39:510-21.
Boceprevir P-gp interaction
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These results suggest that boceprevir is unlikely to have an
inhibitory effect on the P-gp efflux transporter at
concentrations up to 300 μM
However, local concentrations of boceprevir in the gut are
anticipated to reach the limit of solubility (~1.7 mM). The
effect of boceprevir on P-gp at these concentrations is
unknown
This drug interaction study was conducted to assess the
ability of clinically relevant concentrations of boceprevir to
inhibit P-gp using digoxin, a sensitive P-gp substrate
P-gp, P-glycoprotein.
Aims
Primary
– To determine the effect of steady-state
boceprevir on the plasma concentrations of
digoxin in healthy subjects
 Secondary
– To assess the safety and tolerability of multiple
doses of boceprevir and a single dose of digoxin
in healthy subjects

Methods: Study Design

An open-label, randomized cross-over study in
16 healthy adult volunteers
– Treatment A: Digoxin 0.25-mg single dose on day 1
– Treatment B: Boceprevir 800 mg TID for 10 days with
single dose digoxin 0.25 mg on day 6
• 10-day minimum washout period between treatments
– In both treatment periods blood samples for digoxin
pharmacokinetic analysis were collected pre-dose and at
specified time points for 120 hours post-dose
TID, three times daily.
Methods: Subjects
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Adult male and female subjects between 19 and 55 years old
and with BMI 18-33 kg/m2
– Good health based on medical history, physical
examination, vital sign measurements, and laboratory
safety tests
– Female subjects were required to be postmenopausal,
surgically sterilized, or to be using a medically accepted
method of contraception
No clinically significant disease
Negative for hepatitis B surface antigen, hepatitis C
antibodies, and HIV
Provided written informed consent
BMI, body mass index; HIV, human immunodeficiency virus.
Results: Patient Demographics
Male, n = 5; female, n = 11
 White, n = 14; Hispanic/Latino, n = 7
 Mean age, 34 years (range 21 – 50 years)
 Mean BMI, 27 kg/m2 (range 21.7 – 33.0 kg/m2)
 All subjects completed the trial

BMI, body mass index.
Results: Digoxin Pharmacokinetics
Arithmetic Mean Plasma Concentration-Time Profiles of a Single 0.25-mg Dose of Digoxin
Alone or Following Multiple 800-mg Doses of Boceprevir (inset = semi-log scale)
Coadministration of digoxin with boceprevir slightly increased
digoxin AUC0-∞ and Cmax
AUC0-∞, area under the concentration-time curve from time 0 to infinity; Cmax, maximum observed concentration.
Results: Digoxin
Pharmacokinetics (cont)
The geometric mean ratios of AUC0-∞ and Cmax (digoxin + BOC vs digoxin
alone) and the 90% CI were 1.19 (1.12, 1.27) and 1.18 (1.07, 1.31)
AUC0-∞, area under the concentration-time curve from time 0 to infinity; CI, confidence interval; Cmax, maximum observed concentration.
Results: Digoxin
Pharmacokinetics (cont)
Digoxin alone
(n = 16)
Digoxin plus
boceprevir
(n = 16)
Digoxin plus boceprevir /
digoxin alone
GM
95% CI
GM
95% CI
GMR
90% CI
%CVa
AUC0-∞
(ng·h/mL)b
19.32
17.44,
21.40
23.07
21.32,
24.96
1.19
1.12,
1.27
9.623
Cmax (ng/mL)b
0.93
0.78,
1.11
1.10
0.94,
1.28
1.18
1.07,
1.31
16.190
Tmax (h)c
1.5
1.0, 3.0
1.5
1.0, 3.0
—
—
—
t½d
41.4
21.5
45.4
18.8
—
—
—
CL/F (mL/min)d
214.6
18.8
180.1
15.1
—
—
—
The geometric mean (%CV) of the apparent terminal t½ of digoxin were similar (41.4 hours
[21.5%] to 45.4 hours [18.8%] upon coadministration with BOC), indicating that BOC
coadministration does not substantially affect digoxin elimination
AUC0-∞, area under the concentration-time curve from time 0 to infinity; CI, confidence interval; CL/F, apparent clearance; Cmax,
maximum observed concentration; CV, coefficient of variation; GM, geometric mean; GMR, geometric mean ratio, t1/2, apparent
terminal half-life; Tmax, time of maximum observed concentration.
aPseudo within subject %CV. bBack-transformed LS mean and CI from linear effects model performed on log-transformed values.
cMedian (min, max). dGMR (%CV).
Results: Safety
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There were no serious AEs or treatment discontinuations due
to an AE
Twelve patients reported AEs considered to be possibly or
probably related to treatment
AEs
– Digoxin, n = 3 (18.8%):
• Fatigue, n = 1; headache, n = 2
– Boceprevir, n = 9 (56.3%):
• Most common was dysgeusia, n = 8
– Digoxin + boceprevir, n = 10 (62.5%):
• Most common were headache, n = 6, and dysgeusia,
n=5
AE, adverse event.
Conclusions
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Coadministration of digoxin and boceprevir is well tolerated

Digoxin AUC0-∞ and Cmax were slightly increased by 19% and
18%, respectively, when coadministered with boceprevir
800 mg TID at steady state
– This slight increase is not considered clinically important

No dosage adjustment of digoxin is necessary when
coadministered with boceprevir
– Patients receiving concomitant digoxin and boceprevir
should be monitored appropriately

These results also demonstrate that boceprevir has a limited
ability to inhibit P-gp at clinically relevant concentrations
AUC0-∞, area under the concentration-time curve from time 0 to infinity; Cmax, maximum observed concentration;
P-gp, P-glycoprotein; TID, three times daily.
Disclosures
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P Jumes, H-P Feng, F Xuan, J Wagner, J Butterton are all employees of
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.,
Whitehouse Station, NJ, USA
Stephen Youngberg has a financial relationship within the last 12 months
relevant to these data with Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Whitehouse Station, NJ, USA
This study was funded by Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Whitehouse Station, NJ
Acknowledgments
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Medical writing and editorial assistance were provided by Tim Ibbotson,
PhD, and Santo D’Angelo, PhD, MS, of ApotheCom, Yardley, PA. This
assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of
Merck & Co., Inc., Whitehouse Station, NJ