Download Pharmacokinetic Interactions Between the Hepatitis C Virus

HIV/AIDS
MAJOR ARTICLE
Pharmacokinetic Interactions Between the
Hepatitis C Virus Protease Inhibitor Boceprevir
and Ritonavir-Boosted HIV-1 Protease
Inhibitors Atazanavir, Darunavir, and Lopinavir
Ellen G. J. Hulskotte,1 Hwa-Ping Feng,2 Fengjuan Xuan,2 Marga G. J. A. van Zutven,1 Michelle A. Treitel,2
Eric A. Hughes,2 Edward O’Mara,2 Stephen P. Youngberg,3 John A. Wagner,2 and Joan R. Butterton2
1
Merck Sharp & Dohme Corp, Oss, The Netherlands; 2Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, and 3Celerion, Lincoln, Nebraska
Background. Boceprevir represents a new treatment option for hepatitis C (HCV)–infected patients, including
those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs.
Methods. A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and
ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800
mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir
(LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days
10–31, plus concomitant boceprevir on days 25–31.
Results. Boceprevir decreased the exposure of all PI/r, with area under the concentration–time curve [AUC]
from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval
[CI], .55–.78) for ATV/r; 0.66 (90% CI, .60–.72) for LPV/r, and 0.56 (90% CI, .51–.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUCτ) by 22%–36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUCτ was reduced by 45% and 32% when coadministered with
LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events.
Conclusions. Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and
boceprevir. These drug–drug interactions may reduce the effectiveness of PI/r and/or boceprevir when
coadministered.
Keywords. pharmacokinetics; boceprevir; atazanavir; lopinavir; darunavir.
One of the most common comorbidities for patients
with hepatitis C virus (HCV) infection is coinfection
with human immunodeficiency virus (HIV). HCV infection is typically more aggressive in patients with
Received and accepted 2 November 2012; electronically published 15 November 2012.
Presented in part: 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington, 5–8 March 2012.
Correspondence: Ellen Hulskotte, PhD, Department of Clinical Pharmacology,
Merck Research Laboratories, MSD, PO Box 20, 53410 BH Oss, The Netherlands
([email protected]).
Clinical Infectious Diseases 2013;56(5):718–26
© The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cis968
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HIV coinfection [1, 2], with poor response to treatment [3, 4]. Treatment for HCV monoinfection has
advanced with the availability of targeted therapies,
such as boceprevir (BOC), a potent, orally administered, ketoamide serine protease inhibitor (PI) of the
HCV nonstructural protein 3 [5–7].
However, little is known about drug–drug interactions (DDIs) between BOC and commonly prescribed
antiretroviral therapies such as the HIV PIs atazanavir
(ATV), lopinavir (LPV), and darunavir (DRV) [8].
These HIV PIs are inhibitors of, and primarily metabolized by, CYP3A4 [9, 10], and are generally given
in combination with low-dose ritonavir (RTV). Used as
a pharmacokinetic enhancer, RTV is a potent inhibitor
of CYP3A4 and CYP2D6 (to a lesser extent), and
also inhibits several uptake and efflux transporters (such as organic anion-transporting polypeptide and P-glycoprotein) [11, 12].
Moreover, BOC also inhibits CYP3A4/5, raising the possibility
that addition of BOC to RTV-boosted HIV PIs (PI/r) could exacerbate CYP3A4 inhibition.
The current study was designed to investigate the effect of
steady-state BOC on the exposure of RTV-boosted ATV, LPV,
and DRV and vice versa in healthy volunteers, to provide additional guidance for the treatment of HCV/HIV-coinfected
patients.
MATERIALS AND METHODS
Subjects
This was a single-center, randomized, open-label study conducted in accordance with principles of good clinical practice
and approved by the appropriate institutional review board
(Celerion IRB, Lincoln, Nebraska). All subjects provided
written informed consent. Healthy male and female subjects
aged 19–55 years with a body mass index 18–32 kg/m2 were
enrolled. Subjects were required to have no clinically significant disease or abnormal results on physical examination or
laboratory tests and were negative for hepatitis B virus surface
antigen, HCV antibodies, and HIV. Females who were breastfeeding or of childbearing potential and males with partners
intending to become pregnant within 3 months were excluded.
Study Design
Following an overnight fast, all subjects received BOC 800 mg
(4 × 200-mg capsules) every 8 hours for 6 days (Figure 1).
Blood samples for BOC pharmacokinetic analysis were collected predose on the mornings of days 4, 5, and 6, and at 0.5, 1,
2, 3, 4, 6, 8, 10, 12, and 24 hours postdose on day 6. On the
morning of day 10, all subjects initiated PI/r treatment: part 1,
300 mg ATV (Reyataz)/100 mg RTV once daily; part 2, 400
mg LPV/100 mg RTV (Kaletra) twice daily; part 3, 600 mg
DRV/100 mg RTV (Prezista) twice daily. PI/r therapy was
continued from the morning of day 10 until the morning of
day 31; in addition, all subjects received concomitant BOC
800 mg every 8 hours from days 25 to 31. Blood samples for
assessment of PI/r pharmacokinetics were taken predose on
days 10, 18, 23, 28, and 29, and postdose on days 24 and 30 at
0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours, and also at 24 hours
postdose in patients receiving ATV/r (ATV/r only). Additional
blood samples to assess BOC pharmacokinetics were collected
predose on days 29 and 30 and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12,
and 24 hours postdose on day 31.
Both BOC and the HIV-PI/r were taken following food
intake. On each pharmacokinetic sampling day (days 6, 24, 30,
and 31), subjects received a standard breakfast of 860 kcal (46
g fat, 36 g protein, 75 g carbohydrates, 2 g fiber) with observed
dosing after an overnight fast of at least 8 hours. The morning
dose was taken with 240 mL of water 30 minutes after starting
breakfast. Water was restricted 1 hour before and after dosing,
and all subjects fasted for 4 hours after the morning dose. The
use of other medications must have been related to an adverse
event (AE) or to the subject’s medical history. Acetaminophen
( paracetamol) and hormonal contraceptives (except those
containing drospirenone) were allowed.
Assessments
The following pharmacokinetic variables were evaluated for
BOC, RTV, and the HIV PIs: AUClast (area under the concentration–time curve from time 0 to the time of the last measurable sample); AUCτ (area under the concentration–time curve
during a dosing interval τ); Cmax (maximum observed plasma
concentration); Tmax (time to maximum observed plasma concentration); Cmin (minimum observed plasma concentration);
Cl/F (apparent total body clearance); and t½ (terminal phase
half-life). The t½ was determined by linear regression of the
terminal phase of the log-linear concentration–time profiles;
reportable t½ required fitting to at least 3 points in the terminal phase, excluding Cmax. Cl/F was calculated as dose/AUCτ.
For safety monitoring, all AEs were recorded, along with severity, relationship to study drug, and outcome.
Assays
Plasma concentrations of all analytes were determined using validated liquid chromatography with tandem mass spectrometric
detection (PPD, Middleton, Wisconsin). Boceprevir concentrations were determined as the sum of concentrations of 2 enantiomers of BOC, SCH 534128 and SCH 534129. Concentrations
of SCH 629144, an inactive metabolite of BOC, were obtained
as the sum of concentrations of 4 stereoisomers, SCH 783004,
SCH 783005, SCH 783006, and SCH 783007. The overall lower
limit of quantification (LLOQ) for BOC was 4.80 ng/mL, and
the overall LLOQ for SCH 629144 was 2.50 ng/mL. The LLOQ
for HIV PIs and RTV was 10 ng/mL.
Determination of Sample Size
A sample size of 10 volunteers per treatment arm was deemed
adequate based on a within-subject standard deviation of logtransformed Cmax and AUC of BOC of 25% and 20%, respectively, and of log-transformed AUC of the ATV/r, LPV/r, and
DRV/r of 18%, 14%, and 19%, respectively (data on file). The
sample size calculation was based on the ability to show equivalence of the Cmax and AUC between HIV-PI/r alone and with
BOC, using a 90% confidence interval (CI) of .70–1.43 for the
geometric mean ratio (GMR) of the HIV-PI/r and 0.50–2.00
for the GMR of BOC, with two 1-sided tests, and a significance
level (α) of .1 and with at least 80% power. To allow for dropouts, 13 subjects were enrolled in each study arm.
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Table 1.
RESULTS
Patient Demographics
Subject Disposition
Boceprevir + RTV/PI Study
Atazanavir/RTV
(n = 13)
Lopinavir/RTV
(n = 13)
Darunavir/RTV
(n = 13)
4 (31)
9 (69)
5 (38)
8 (62)
5 (38)
6 (62)
9 (69)
4 (31)
9 (69)
4 (31)
13 (100)
0
4 (31)
2 (15)
9 (69)
11 (85)
13 (100)
36.3 (7.4)
33.1 (11.0)
37.3 (13.3)
27.5 (3.8)
26.3 (3.1)
25.2 (3.4)
Sex, No. (%)
Female
Male
Boceprevir/Atazanavir/Ritonavir Pharmacokinetics
Race, No. (%)
White
Nonwhite
Ethnicity, No. (%)
Hispanic/
Latino
Non-Hispanic/
Latino
Age, y, mean
(SD)
BMI, kg/m2,
mean (SD)
Thirty-nine subjects were enrolled and randomized to ATV/r
(n = 13), LPV/r (n = 13), or DRV/r (n = 13) treatment. Baseline demographics were generally similar across treatment
arms (Table 1).
0
Abbreviations: BMI, body mass index; PI, protease inhibitor; RTV, ritonavir;
SD, standard deviation.
Statistical Analyses
A mixed-effects model including factors for subject and treatment was employed. The GMRs and associated 90% CIs for
log-transformed AUCs were analyzed, extracting the effect
due to treatment as fixed effect and subject as random effect.
The resulting 2-sided 90% CI for the true mean difference in
AUC0-last values was then exponentiated to obtain the CI for
true GMR.
Mean ATV concentrations were lower at all time points in the
presence of BOC than with ATV/r alone (Figure 2A). Cmax,
AUClast, and AUCτ for ATV were lower in subjects receiving
BOC plus ATV/r compared with ATV/r alone: at steady state,
ATV AUC0-last, Cmax, and Cmin values were reduced by 35%,
25%, and 49%, respectively (Tables 2 and 3). Geometric mean
ATV Cmin was decreased from 693 ng/mL to 333 ng/mL in
the presence of BOC.
By contrast, BOC pharmacokinetics were largely unchanged
in the presence of ATV/r; ATV/r had little effect on BOC exposure and Cmax (Tables 2 and 3). An approximate 18% decrease in BOC Cmin was seen upon coadministration with
ATV/r (Table 3). Ritonavir AUCτ and Cmax were reduced by
36% and 27%, respectively, in the presence of BOC and ATV,
compared with ATV alone (Table 3, Figure 3).
Boceprevir/Lopinavir/Ritonavir Pharmacokinetics
Mean LPV concentrations were lower at all time points in the
presence of BOC and RTV than with RTV alone (Figure 2B).
Geometric mean ratios for LPV AUC0-last, Cmax, and Cmin
were reduced 34%, 30%, and 43%, respectively, in the presence
of BOC plus LPV/r, compared with LPV/r alone. Geometric
Figure 1. Study design for boceprevir/ritonavir/human immunodeficiency virus protease inhibitor coadministration. Abbreviations: ATV, atazanavir; bid,
twice daily; BOC, boceprevir; DRV, darunavir; HIV, human immunodeficiency virus; LPV, lopinavir; PI, protease inhibitor; PK, pharmacokinetic; qd, once
daily; RTV, ritonavir; tid, 3 times daily.
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in the presence of BOC (Table 2), with GMR of DRV AUC0last, Cmax, and Cmin reduced by 44%, 36%, and 59%, respectively, when coadministered with BOC plus RTV compared with
RTV alone. Geometric mean DRV Cmin decreased from 3222
ng/mL to 1321 ng/mL with BOC coadministration (Table 5).
Boceprevir exposure was markedly reduced when coadministered with DRV/r (Table 2). GMRs for BOC were reduced
by 32% for AUCτ, 25% for Cmax, and 35% for Cmin when administered with DRV/r (Table 5). Ritonavir exposure was
reduced by 27% and Cmax by 13% in subjects receiving BOC
plus DRV/r compared with those receiving DRV alone
(Table 5, Figure 3).
Safety
Figure 2. Mean (standard deviation) plasma concentration–time profiles for ritonavir-boosted atazanavir (A), lopinavir (B ), and darunavir (C )
alone and in combination with boceprevir. Abbreviations: ATV, atazanavir;
BOC, boceprevir; DRV, darunavir; LPV, lopinavir; MD, multiple dose; RTV,
ritonavir.
mean LPV Cmin was decreased from 6730 ng/mL to 3805 ng/
mL by the presence of BOC.
Coadministration of BOC with LPV/r reduced BOC concentrations (Table 2). Overall, BOC AUCτ, Cmax, and Cmin
GMRs decreased between 45% and 57% when BOC was coadministered with LPV/r (Table 4). Geometric least-squares
mean BOC Cmin decreased from 92 ng/mL to 40 ng/mL with
LPV/r coadministration. Ritonavir AUCτ and Cmax were
reduced by 22% and 12%, respectively, in the presence of BOC
and LPV compared with LPV alone (Table 4, Figure 3).
Boceprevir/Darunavir/Ritonavir Pharmacokinetics
Mean DRV concentrations were lower at all time points in the
BOC plus DRV/r treatment arm than with DTV/r alone
(Figure 2C). Darunavir Cmax, AUC0-last, and AUCτ were lower
There were no deaths, severe/serious AEs, or clinically relevant
changes in hematology, blood pressure, pulse rate, oral body
temperature, or electrocardiogram parameters. In the ATV/r
group, 1 subject stopped treatment because of an increase in
total bilirubin (7.6 mg/dL; 4.75 × upper limit of normal) with
apparent jaundice, blurred vision, and dizziness after receiving
ATV/r for 5 days. A second subject withdrew consent for personal reasons. In total, 80 AEs were reported by 10 of 13 subjects, with 72 categorized as possibly/probably drug related.
The most common drug-related AE was dysgeusia (n = 8). All
AEs were mild in intensity except for 1 report of elevated bilirubin and another of dyspepsia, both of moderate intensity.
In the LPV/r group, a total of 129 AEs were reported by 12
of 13 subjects, with 104 considered to be possibly/probably
drug related. There were no treatment discontinuations, and
the most common drug-related AEs were dysgeusia (n = 10)
and headache (n = 5). All AEs were of mild intensity except
for 1 case of headache of moderate intensity.
In the DRV/r group, a total of 111 AEs were reported
across all 13 subjects, with 80 considered to be possibly/probably drug related. Two subjects in the DRV/r group discontinued because of an AE (abdominal cramp, n = 1; nausea, n = 1;
both moderate intensity), and all subjects reported at least 1
possible/probable drug-related AE (most commonly dysgeusia
[n = 12] and dizziness [n = 5]). All AEs were of mild intensity
except the cases of abdominal cramping and nausea leading to
treatment discontinuation.
DISCUSSION
Data from the present study indicate that coadministration
with BOC reduces the concentrations of RTV and RTVboosted ATV, LPV, and DRV. Boceprevir reduced mean
trough concentrations of ATV/r, LPV/r, and DRV/r by 49%,
43%, and 59%, respectively. Mean reductions in HIV PI exposure ranged from 34% to 44%, and PI Cmax decreased from
25% to 36%. RTV exposure was also reduced in the presence
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Table 2. Pharmacokinetic Parameters for Boceprevir, and Ritonavir-Boosted Atazanavir, Lopinavir and Darunavir, Geometric Means
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Treatment
Cmax (ng/mL)
AUClast (ng × h/mL)
AUCτ (ng × h/mL)
Cmin (ng/mL)
t½ (h)
CL/F (L/h)
Tmax a (h)
ATV/RTV + BOC
ATV PK
•
ATV/RTV alone
3606 (37.7) n = 12
39 932 (31.9) n = 12
36 202 (31.3) n = 8
693 (52.8) n = 12
11.1 (26.5) n = 8
138 (31.2) n = 8
4.0 (2.0–8.0) n = 12
ATV/RTV + BOC
BOC PK
2641 (22.9) n = 11
25 762 (18.1) n = 11
24 272 (13.1) n = 9
333 (48.9) n = 11
10.2 (39.6) n = 9
206.0 (13.1) n = 9
4.0 (3.0–7.9) n = 11
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BOC alone
1450 (36.7) n = 13
5615 (22.8) n = 13
4835 (26.1) n = 13
106 (40.4) n = 13
2.9 (67.8) n = 12
2758 (26.1) n = 13
4.0 (3.0–6.0) n = 13
BOC + ATV/RTV
RTV PK
1400 (27.7) n = 11
5270 (25.0) n = 11
4687 (23.8) n = 11
86 (33.1) n = 11
3.6 (88.0) n = 9
2845 (23.8) n = 11
4.0 (2.0–6.0) n = 11
ATV/RTV alone
1474 (31.7) n = 12
9269 (33.9) n = 12
9274 (33.9) n = 12
35.8 (80.6) n = 12
5.0 (17.2) n = 12
180 (33.9) n = 12
4.0 (2.0–4.0) n = 12
1049 (25.6) n = 11
5807 (30.4) n = 11
5857 (29.5) n = 11
22.7 (41.6) n = 8
4.6 (27.6) n = 11
285 (29.5) n = 11
4.0 (3.0–4.0) n = 11
13 305 (18.8) n = 13
9375 (23.1) n = 13
117 200 (24.0) n = 13
77 082 (23.1) n = 13
108 953 (22.0) n = 8
77 436 (23.2) n = 13
6,730 (40.0) n = 13
3805 (33.7) n = 13
9.0 (45.8) n = 8
5.5 (35.3) n = 13
61 (22.0) n = 8
86 (23.2) n = 13
4.0 (3.0–8.0) n = 13
4.0 (2.0–6.0) n = 13
1767 (47.4) n = 13
878 (55.2) n = 13
6513 (65.1) n = 13
3677 (64.9) n = 13
6040 (61.9) n = 13
3315 (62.7) n = 13
2.8 (86.6) n = 10
2.3 (76.8) n = 12
2207 (61.9) n = 13
4023 (62.6) n = 13
4.0 (3.0–4.0) n = 13
4.0 (0.5–6.0) n = 13
990 (44.1) n = 13
869 (60.1) n = 13
5518 (33.8) n = 13
4258 (43.9) n = 13
5360 (33.0) n = 12
4268 (43.9) n = 13
155 (51.4) n = 13
91 (54.8) n = 13
3.1 (25.2) n = 12
2.8 (25.5) n = 13
311 (33.1) n = 12
391 (43.9) n = 13
4.0 (3.0–6.0) n = 13
4.0 (3.0–6.0) n = 13
8086 (23.4) n = 11
60 271 (24.6) n = 11
59 943 (19.8) n = 5
3222 (32.1) n = 10
9.3 (30.2) n = 5
167 (19.8) n = 5
3.0 (2.0–4.0) n = 11
5192 (25.0) n = 11
33 511 (22.2) n = 11
33 319 (23.2) n = 10
1321 (26.3) n = 11
5.9 (32.1) n = 10
300 (23.2) n = 10
3.0 (1.0–4.0) n = 11
1564 (29.1) n = 12
5940 (22.8) n = 12
5352 (21.2) n = 12
95 (36.6) n = 12
3.6 (54.7) n = 11
2491 (21.2) n = 12
3.5 (3.0–6.0) n = 12
1161 (20.1) n = 11
4149 (22.0) n = 11
3600 (17.0) n = 11
62 (25.8) n = 11
5.1 (60.9) n = 8
3603 (17.0) n = 11
3.0 (1.0–4.0) n = 11
776 (36.9) n = 11
4816 (31.0) n = 11
4829 (30.9) n = 11
155 (28.6) n = 11
3.7 (19.6) n = 11
345 (30.9) n = 11
4.0 (2.0–6.0) n = 11
678 (53.6) n = 11
3552 (36.8) n = 11
3375 (33.3) n = 10
86 (31.1) n = 11
4.0 (20.1) n = 10
494 (33.3) n = 10
4.0 (3.0–6.0) n = 11
ATV/RTV + BOC
LPV/RTV + BOC
LPV PK
LPV/RTV alone
LPV/RTV + BOC
BOC PK
BOC alone
BOC + LPV/RTV
92 (115.6) n = 13
40 (123.7) n = 12
RTV PK
LPV/RTV alone
LPV/RTV + BOC
DRV/RTV + BOC
DRV PK
DRV/RTV alone
DRV/RTV + BOC
BOC PK
BOC alone
BOC + DRV/RTV
RTV PK
DRV/RTV alone
DRV/RTV + BOC
All data, except for Tmax, are presented as geometric mean (coefficient of variance). For some of the subjects, AUCτ, t½, and Cl/F could not be reported because there was insufficient number of points after Cmax to
define the terminal phase.
Abbreviations: ATV, atazanavir; AUClast, area under the concentration–time curve to the last measureable sample; AUCτ, area under the concentration–time curve during a dosing interval τ; BOC, boceprevir; Cmax,
maximum observed plasma concentration; Cmin, minimum observed plasma concentration; Cl/F, apparent clearance; DRV, darunavir; LPV, lopinavir; PK, pharmacokinetics; RTV, ritonavir; t½, apparent terminal halflife; Tmax, time to maximum observed plasma concentration.
a
Data presented as median (range).
Table 3. Pharmacokinetic Interactions Among Boceprevir,
Atazanavir, and Ritonavir
PK Parameter
No.
ATV PK
90% CI
rMSEa
(BOC + ATV/RTV)/(ATV/RTV)
AUC0-lastb,c (ng × h/mL)
Cmax b (ng/mL)
12
12
Cmin b (ng/mL)
12
BOC PK
AUCτ b (ng × h/mL)
GMR
13
Cmax b (ng/mL)
13
Cmin b (ng/mL)
RTV PK
13
0.65
0.75
(.55–.78)
(.64–.88)
0.23
0.21
0.51
(.44–.61)
0.22
(BOC + ATV/RTV)/(BOC)
0.95
(.87–1.05)
0.93
(.80–1.08)
0.12
0.20
0.82
(.68–.98)
0.25
(BOC + ATV/RTV)/(ATV/RTV)
AUCτ b (ng × h/mL)
12
0.64
(.58–.72)
0.14
Cmax b (ng/mL)
Cmin b (ng/mL)
12
12
0.73
0.55
(.64–.83)
(.45–.67)
0.17
0.21
Abbreviations: ATV, atazanavir; AUC0-last, area under the concentration–time
curve to the last measurable sample; AUCτ, area under the concentration–
time curve during a dosing interval τ; BOC, boceprevir; CI, confidence
interval; Cmax, maximum observed plasma concentration; Cmin, minimum
observed plasma concentration; GMR, geometric least-squares mean ratio;
PK, pharmacokinetics; RTV, ritonavir.
a
rMSE: Square root of conditional mean squared error (residual error) from
the linear mixed-effect model. rMSE*100% approximates the within-subject
coefficient of variation (%CV) on the raw scale.
b
Back-transformed least-squares mean and CI from linear mixed-effect
model performed on natural log-transformed values.
c
Statistical comparison was conducted using AUC0-last as several subjects
did not have reportable AUCτ. As the actual sampling time point did not
deviate >1% from the dosing interval τ, AUC0-last accurately represented
AUCτ.
of HIV PIs and BOC (22%–36%). Furthermore, although
BOC exposure was unchanged by ATV/r coadministration,
BOC AUCτ was reduced by 45% and 32% by LPV/r and
DRV/r, respectively. A previous DDI study between BOC and
RTV alone indicated that the exposure of BOC (400 mg every
8 hours) was reduced by 19% when coadministered with RTV
(100 mg once daily; AUCτ GMR, 0.81 [90% CI, .73–.91]), with
an associated 27% reduction in BOC Cmax (GMR, 0.73 [90%
CI, .57–.93]) [13].
The observed pharmacokinetic interactions cannot be explained solely by a CYP3A4/5-mediated interaction or a reduction of RTV levels by BOC leading to a decrease in the
RTV-mediated boosting of the HIV PI concentrations. In addition to potently inhibiting CYP3A, RTV inhibits several
uptake and efflux transporters and can induce various drugmetabolizing enzymes, including CYP3A [9, 10]. Boceprevir
and the HIV PIs evaluated in this study inhibit some of the
same drug-metabolizing enzymes and transporters [11, 12].
Because of the complex enzyme-transporter interplay and potential mechanisms of interaction among the 3 components
(HIV PI, RTV, and BOC), it is not possible to isolate the relative contribution of each pathway to the observed interactions.
In addition, the role of protein displacement or altered
Figure 3. Mean (standard deviation) plasma concentration–time profiles for ritonavir in combination with atazanavir (A), lopinavir (B ), or darunavir (C ) in the presence and absence of boceprevir. Abbreviations:
ATV, atazanavir; BOC, boceprevir; DRV, darunavir; LPV, lopinavir; MD,
multiple dose; RTV, ritonavir.
absorption cannot be excluded. Exposure of the inactive ketoreduced metabolite of BOC, SCH 629144 (a product of
aldoketo-reductase-mediated metabolism), was increased by
all HIV PIs/r by approximately 1- to 2-fold (data on file). As
the HIV PIs and RTV inhibit both drug-metabolizing enzyme
and uptake/efflux transporter systems, our data do not clarify
whether the increase in SCH 629144 levels is due to increased
keto-reduced metabolite formation, reduced elimination of
SCH 629144, or a combination of both.
The findings from this study do not indicate whether the
reduced drug exposures observed in healthy volunteers will
impact clinical efficacy. The lower limit of the 90% CI for the
effect of BOC on ATV, LPV, and DRV fell below the bounds
of .70–1.43 generally used to indicate clinically relevant effects
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Table 4. Pharmacokinetic Interactions Among Boceprevir,
Lopinavir, and Ritonavir
PK Parameter
No.
LPV PK
GMR
90% CI
rMSEa
(BOC + LPV/RTV)/(LPV/RTV)
Table 5. Pharmacokinetic Interactions Among Boceprevir,
Darunavir, and Ritonavir
PK Parameter
No.
DRV PK
13
13
0.66
0.70
(.60–.72)
(.65–.77)
0.13
0.12
AUC0-last b,c (ng × h/mL)
Cmax b (ng/mL)
11
11
Cmin b (ng/mL)
13
0.57
(.49–.65)
0.19
Cmin b (ng/mL)
10
13
Cmax b (ng/mL)
13
Cmin b (ng/mL)
RTV PK
13
AUCτ b (ng × h/mL)
b
Cmax (ng/mL)
Cmin b (ng/mL)
(BOC + LPV/RTV)/(BOC)
0.55
(.49–.61)
0.15
BOC PK
AUCτ b (ng × h/mL)
12
0.15
Cmax b (ng/mL)
12
0.43
(.36–.53)
0.27
(BOC + LPV/RTV)/(BOC)
Cmin b (ng/mL)
RTV PK
12
0.50
(.45–.55)
90% CI
rMSEa
(BOC + DRV/RTV)/(DRV/RTV)
AUC0-last b,c (ng × h/mL)
Cmax b (ng/mL)
BOC PK
AUCτ b (ng × h/mL)
GMR
0.56
0.64
(.51–.61)
(.58–.71)
0.12
0.13
0.41
(.38–.45)
0.11
(BOC + DRV/RTV)/(BOC)
0.68
(.65–.72)
0.072
0.75
(.67–.85)
0.16
0.65
(.56–.76)
0.20
(BOC + DRV/RTV)/(BOC)
12
0.78
(.71–.87)
0.15
AUCτ b (ng × h/mL)
11
0.73
(.68–.79)
0.092
13
13
0.88
0.58
(.72–1.07)
(.52–.65)
0.28
0.16
Cmax b (ng/mL)
Cmin b (ng/mL)
11
11
0.87
0.55
(.76–1.00)
(.52–.59)
0.18
0.077
Abbreviations: AUC0-last, area under the concentration–time curve to the last
measurable sample; AUCτ, area under the concentration–time curve during a
dosing interval τ; BOC, boceprevir; CI, confidence interval; Cmax, maximum
observed plasma concentration; Cmin, minimum observed plasma
concentration; GMR, geometric least-squares mean ratio; LPV, lopinavir; PK,
pharmacokinetics; RTV, ritonavir.
Abbreviations: AUC0-last, area under the concentration–time curve to the last
measurable sample; AUCτ, area under the concentration–time curve during a
dosing interval τ; BOC, boceprevir; CI, confidence interval; Cmax, maximum
observed plasma concentration; Cmin, minimum observed plasma
concentration; DRV, darunavir; GMR, geometric least-squares mean ratio; PK.
pharmacokinetics; RTV, ritonavir.
a
rMSE: Square root of conditional mean squared error (residual error) from
the linear mixed-effect model. rMSE*100% approximates the within-subject
%CV on the raw scale.
a
b
Back-transformed least-squares mean and CI from linear mixed–effect
model performed on natural log-transformed values.
b
Back-transformed least-squares mean and CI from linear mixed-effect
model performed on natural log-transformed values
c
Statistical comparison was conducted using AUC0-last as several subjects
did not have reportable AUCτ. As the actual sampling time point did not
deviate >1% from the dosing interval τ, AUC0-last accurately represented
AUCτ.
c
Statistical comparison was conducted using AUC0-last as several subjects
did not have reportable AUCτ. As the actual sampling time point did not
deviate >1% from the dosing interval τ, AUC0-last accurately represented
AUCτ.
for this class of compounds [14–16]. For BOC, the 90% CIs
were within the clinically relevant range of .5–2.0 for the interaction with ATV/r and DRV/r, but not for LPV/r. Furthermore, compromised liver function resulting from HCV
infection should be considered when translating these results
to patients, as liver function may impact drug metabolism and
therapeutic levels [17].
Data regarding the use of BOC-based treatment for HCV
genotype 1 infection in patients coinfected with HIV are currently limited [18]. The pharmacokinetic interactions observed
in healthy volunteer studies do not appear to have a substantial clinical impact in patients with HIV/HCV coinfection.
Interim data from treatment-naive patients with HCV genotype 1 infection and HIV coinfection suggest that sustained
virologic response (SVR) 12 rates (undetectable HCV-RNA 12
weeks posttreatment) are significantly higher in patients receiving BOC plus peginterferon/ribavirin (PR) than in those
receiving placebo plus PR alone (61% vs 27%) [19]. In this
study, 28 of 34 patients receiving PR and 45 of 61 patients
receiving BOC plus PR received concomitant ATV/r, LPV/r,
or DRV/r, and SVR rates were generally similar between these
patients and those receiving alternative HIV antiviral therapy.
It is possible that SVR rates may have been even higher with
other background antiretroviral medications that did not
affect BOC levels. However, there is no reported correlation
between BOC exposure and SVR rates in either monoinfected
patients in previous phase 3 trials or in HIV/HCV-coinfected
patients [20]. Treatment failure (HCV RNA <2 log decline at
week 12 or detectable at week 24) was higher in the placebo
arm (41% vs 9%). All patients had HIV RNA levels <50
copies/mL and a CD4 cell count >200 cells/μL at baseline.
During the study, 4 of 34 patients (12%) receiving placebo and
3 of 64 patients (5%) receiving BOC experienced HIV viral
rebound (>50 copies/mL at 2 consecutive visits) [19]. It may
be that the potentially adverse impact of a BOC-boosted PI
drug–drug interaction was mitigated by a beneficial anti-HIV
effect of peginterferon alfa. An important caveat is that this
was a small study with 64 of 98 patients receiving BOC.
Further studies are needed to confirm these findings and
better define the role of BOC in this setting. Currently, BOC is
not approved for treatment of HIV/HCV-coinfected patients.
Guidelines are emerging that pertain to treatment of the coinfected population and are likely to evolve as more data
become available [8, 18, 21, 22].
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rMSE: Square root of conditional mean squared error (residual error) from
the linear mixed-effect model. rMSE*100% approximates the within-subject
%CV on the raw scale.
Drug–drug interactions between BOC and other antiretroviral therapies have also been studied. Boceprevir had no impact
on the exposure of the integrase inhibitor raltegravir [23]. Boceprevir also had no notable effect on the AUC or renal clearance of tenofovir, although tenofovir Cmax was increased by
32% [24]. Efavirenz AUC0–24 and Cmax were increased by 20%
and 11%, respectively, in the presence of BOC [24], whereas
etravirine AUCτ, Cmax, and Cmin were reduced by 23%, 24%,
and 29%, respectively, in the presence of BOC [25]. Tenofovir
had no clinically relevant effect on BOC pharmacokinetics, increasing BOC AUC and Cmax by 8% and 5%, respectively [24].
When coadministered with efavirenz, BOC AUC and Cmax
were decreased 8% and 19%, respectively, and Cmin was decreased 44% [24]. When coadministered with etravirine, BOC
AUCτ and Cmax were increased 10%, while C8hours was decreased 12% by etravirine [25]. Clinicians must consider the
additive effects of interactions with other concomitantly administered drugs when determining the clinical impact of
combination drug use.
In addition to small sample size, limitations of the current
study may also include use of a fixed-sequence design rather
than a randomized crossover design. As LPV, DRV, and RTV
have the potential to induce CYP450 enzymes [14, 26, 27], a
crossover design would require an extra washout period of 2
weeks to restore enzyme levels to baseline, extending study duration to over 6 weeks. To allow full enzyme induction, HIVPI/r treatment was initiated 21 days before blood sampling for
assessment of BOC pharmacokinetics. The short half-life of
BOC and the lack of induction seen in vitro and in vivo [28]
suggest that the risk of carryover effects with the current
design were minimal.
In conclusion, concomitant administration of BOC with PI/r
reduced exposures of the HIV PIs, RTV, and BOC. The current
study raises no toxicity-related safety concerns; however, the
drug–drug interactions may potentially reduce the effectiveness
of these HIV therapies and/or of BOC. Additional data on concomitant administration in HCV/HIV-coinfected patients are
needed to provide appropriate guidance for the treatment of
these patients.
Notes
Acknowledgments. Bioanalytical support was provided by Bhavana
Kantesaria (employee of Merck Sharp & Dohme Corp), and pharmacokinetic and statistical support was provided by Megan Kozisek of Celerion
(assistance supported by Merck Sharp & Dohme Corp). Medical writing
and/or editorial assistance were provided by Tim Ibbotson, PhD, and
Santo D’Angelo, PhD, MS, of ApotheCom. This assistance was funded by
Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
Financial support. This study was funded by Merck Sharp & Dohme
Corp, a subsidiary of Merck & Co, Inc.
Potential conflicts of interest. S. P. Y. has a financial relationship
within the last 12 months relevant to these data with Merck Sharp &
Dohme Corp, a subsidiary of Merck & Co, Inc. M. T., E. A. H., H. P. F.,
F. X., E. O., J. W., and J. B. are current or former employees of Merck
Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. E. H. and
M. V. are current or former employees of Merck Sharp & Dohme, the
Netherlands.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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