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Antiviral Therapy 12:509–514
Pharmacokinetic interaction between TMC114/r and
efavirenz in healthy volunteers
Vanitha J Sekar1*, Martine De Pauw2, Kris Mariën2, Monika Peeters2, Eric Lefebvre1 and
Richard MW Hoetelmans2
1
Tibotec, Inc., Yardley, PA, USA
Tibotec BVBA, Mechelen, Belgium
2
*Corresponding author: Tel: +1 609 730 7500; Fax: +1 609 730 7501; E-mail: [email protected]
Background: This open-label, crossover study investigated
the pharmacokinetic interaction between TMC114
(darunavir [Prezista™]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative,
healthy volunteers.
Methods: Volunteers received TMC114/r 300/100 mg
twice daily for 6 days, and once daily on day 7 (session
1). After a 7-day washout period volunteers received EFV
600 mg once daily for 18 days (session 2), with
coadministration of TMC114/r 300/100 mg twice daily
from day 11–day 16 and TMC114/r once daily on day 17.
Results: When coadministered with TMC114/r, plasma
concentrations of EFV were slightly increased. In the
presence of TMC114/r, EFV minimum (Cmin) and maximum
(Cmax) plasma concentrations increased by 15–17%, and
by 21% for EFV area under the curve (AUC24h). TMC114/r
and EFV coadministration resulted in TMC114 Cmin, Cmax
and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to
withdrawal were reported in this trial. Overall, TMC114/r
and EFV coadministration was well tolerated.
Conclusions: The clinical significance of the changes in AUC
and Cmin seen with TMC114/r and EFV coadministration has
not been established; this combination should be used with
caution. Similar findings are expected with the approved
TMC114/r 600/100 mg twice daily dose.
Introduction
Guidelines for the treatment of HIV-infected individuals
recommend the first-line use of two nucleoside reverse
transcriptase inhibitors (NRTIs) with either a protease
inhibitor (PI, generally boosted) or a non-nucleoside
reverse transcriptase inhibitor (NNRTI) in
antiretroviral-naive patients [1–3]. The two most
widely used NNRTIs are efavirenz (EFV) and nevirapine, which showed comparable antiviral efficacy in
a large open-label, randomized trial in treatment-naive
patients with chronic HIV infection [4]. Treatmentexperienced patients who have failed to respond to
first-line PI therapy due to the emergence of virological
resistance may require optimized regimens including
both NNRTIs and PIs. Combining a PI with an
NNRTI has been successful in nucleoside-experienced
patients. Thus, in the AIDS Clinical Trials Group
(ACTG) 364 study a quadruple regimen including
nelfinavir and EFV and two NRTIs provided a greater
likelihood of achieving virological suppression at 144
weeks than a triple antiretroviral regimen including
either nelfinavir or EFV [5]. However, the benefits
observed with such a quadruple regimen, containing
both a PI and an NNRTI, must be balanced with the
potential tolerability issues observed with this combination [6]. The combined use of NNRTIs and PIs has
© 2007 International Medical Press 1359-6535
also been confirmed as a promising strategy in singlePI-experienced patients, although direct comparative
studies with other optimized regimens are lacking [7].
Data (24-week) from the noncomparative Bitherapy
Kaletra Sustiva (BIKS) study, which includes both
treatment-experienced and treatment-naive patients,
have suggested that the NRTI-sparing regimen of
boosted lopinavir/EFV may provide effective antiviral
and immunological activity with acceptable tolerability
[8]. ACTG 5142 compared EFV plus NRTIs with a
lopinavir/ritonavir (LPV/r) plus NRTIs regimen, and it
also compared these two regimens to a regimen of only
LPV/r and EFV (without NRTIs) [9]. Compared with a
regimen of EFV + NRTIs, LPV/r + NRTIs had a significantly shorter time to virological failure. At
96 weeks, the NRTI-sparing regimen of LPV/r + EFV
had similar virological efficacy and similar time to
treatment-limiting toxicity as EFV + NRTIs.
In general, PIs are rapidly absorbed and extensively
metabolized primarily via cytochrome P450 (CYP)
3A4 pathways. NNRTIs lower the plasma concentrations of PIs [10–12] mainly by induction of CYP3A4
metabolism; this induction can be reversed by
coadministration of low-dose ritonavir (RTV) [13,14].
Interactions with NNRTIs differ considerably amongst
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VJ Sekar et al.
PIs and predicting the direction or size of potential
interactions a priori can be difficult.
TMC114 (darunavir, [Prezista™]) is a novel PI,
highly active against both wild-type and resistant HIV1 strains in vitro, including a broad range of over 4,000
clinical isolates [15,16]. TMC114 has received its first
regulatory approvals for the treatment of HIV infection
in treatment-experienced adult patients, such as those
with HIV-1 strains resistant to more than one PI [17].
TMC114 is a substrate for CYP3A4 metabolism [18],
and an inhibitor of this enzyme. In HIV-negative,
healthy volunteers, coadministration of TMC114 as a
polyethylene glycol (PEG) 400-containing oral solution
with low-dose RTV (TMC114/r) resulted in an
improved pharmacokinetic profile compared with
TMC114 alone [19].
An interaction with NNRTIs may significantly lower
the exposure to TMC114, and thereby lower the efficacy of TMC114/r. Given the possible future use of
TMC114/r in combination with EFV in clinical practice, the present study was performed to assess the
potential for a pharmacokinetic interaction and to
determine whether dose adjustments may be required
during coadministration. Short-term safety and tolerability of the coadministration of TMC114/r with EFV
was also assessed.
Materials and methods
Study population and study design
This was an open-label, crossover study to investigate
the pharmacokinetic interaction between TMC114,
coadministered with low-dose RTV (TMC114/r), and
EFV. The study participants were 12 HIV-negative,
healthy volunteers aged 18–55 years. During session 1,
volunteers received 300 mg TMC114 and 100 mg RTV
(TMC114/r 300/100 mg) twice daily for 6 days with an
additional dose in the morning of day 7. Following a
7-day washout period, volunteers received 600 mg EFV
once daily in the morning for 18 days (session 2).
TMC114/r 300/100 mg twice daily was coadministered
with EFV 600 mg once daily from day 11 until day 16,
with an additional single dose of TMC114/r 300/100
mg given on day 17. In this study, EFV was taken with
or without food and TMC114/r was taken with food.
TMC114 was formulated as an oral aqueous solution
(20 mg/ml TMC114 containing D-α-tocopheryl polyethylene glycol 1000 succinate and PEG 400 as main
solubilizing agents), while RTV (100 mg) and EFV (3×
200 mg) were given as commercially available capsules.
Dosing of study medication by the volunteers at home
was performed according to a predefined schedule;
times of study drug administration and meal times were
recorded in a diary. On day 7 of session 1 and days 10
and 17 of session 2, when samples were taken for
510
pharmacokinetic analysis, study drugs had to be taken
within 15 min of completing a standard breakfast.
The study protocol was reviewed and approved by
the appropriate institutional ethics committee(s) and
health authorities, and was conducted in accordance
with the Declaration of Helsinki. Written informed
consent was obtained from all volunteers.
Pharmacokinetic assessments
Serial venous blood samples were drawn over the
dosing interval for TMC114, RTV and EFV. Plasma
concentrations of TMC114, RTV and EFV were determined using validated liquid chromatography tandem
mass spectrometry methods. The lower limit of quantification was 10.1 ng/ml for TMC114, 5.0 ng/ml for
RTV and 50.0 ng/ml for EFV.
On days 12, 14 and 16 of session 2 both TMC114/r
and EFV predose concentrations were determined. On
days 17, 18 and 19 of session 2, TMC114 and RTV
plasma concentrations were determined in samples
taken predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 24,
36 and 48 h postdose. On day 17 of session 2, EFV
concentrations were determined in samples taken
predose and at 1, 2, 3, 4, 5, 6, 9, 12 and 24 h postdose.
Safety evaluations
Volunteers were monitored regularly throughout the
study for cardiovascular parameters and biochemical
characteristics of blood and urine. In addition, fasted
blood lipid values were evaluated. The investigator
scored the severity of adverse events (AEs) as mild,
moderate, severe, or (potentially) life-threatening.
Laboratory safety blood samples were obtained on
days 1, 4 and 7 of session 1 and days 1, 4, 7, 10, 12,
14, 17 and 19 of session 2. All safety evaluations were
graded according to the ACTG severity grading scales.
Statistical methods
Descriptive statistics were calculated for the plasma
concentrations of TMC114, RTV and EFV, and the
urinary concentrations of TMC114. WinNonlin
Professional™ (version 3.3; Pharsight Corp., Mountain
View, CA, USA) was used for pharmacokinetic analysis.
The pharmacokinetic parameters were determined by
noncompartmental methods and included the area
under the curve over the dose interval (AUC12h or
AUC24h), minimum (Cmin) and maximum (Cmax) plasma
concentrations, time to maximum plasma concentration (tmax), terminal elimination half-life defined as
0.693/λz (t1/2term), and elimination rate constant (λz).
Comparison of the pharmacokinetic parameters
Cmin, Cmax and AUC12h of TMC114/r with and without
concomitant EFV and comparison of the pharmacokinetic parameters of Cmin, Cmax and AUC24h of EFV
with and without concomitant TMC114/r were
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PK interaction of TMC114/r and efavirenz
Of the 22 volunteers screened, 12 were assigned to
treatment and completed the study. The median age
was 42 years (range: 20–54) and four of the volunteers were female. The median (range) in body weight
was 71.5 (64–90) kg and median (range) body mass
index was 24.6 (20–29) kg/m2. One volunteer
received 10 mg domperidone on day 10 of session 2
during treatment with EFV alone, and was included in
the pharmacokinetic analysis.
Pharmacokinetic data
Mean plasma concentration–time curves of TMC114
and EFV are shown in Figures 1A and B, respectively.
Mean TMC114 plasma concentrations were decreased
while those of EFV were increased following
coadministration of EFV and TMC114/r. However,
median TMC114 or EFV tmax was not influenced by
coadministration of the two compounds. Mean
pharmacokinetic parameters determined for TMC114
are shown in Table 1.
Predose plasma concentrations of TMC114 were
comparable between days 4, 6 and 7 of session 1 and
between days 14, 16 and 17 of session 2, showing
achievement of steady-state prior to pharmacokinetic
assessments. The mean t1/2term of TMC114 was decreased
by approximately 50% after coadministration of EFV,
from 12.5 ±4.8 to 5.0 ±1.1 h. Mean TMC114 Cmax and
AUC12h were decreased by 15% (LS means ratio, 90%
CI: 0.85, 0.72–1.00) and 13% (LS means ratio, 90% CI:
0.87, 0.75–1.01), respectively, and mean Cmin was
decreased by 31% (LS means ratio, 90% CI: 0.69,
0.54–0.87), respectively (Table 1).
EFV AUC24h was increased by 21% (LS means ratio,
90% CI: 1.21, 1.08–1.36), Cmin by 17% (LS means
ratio, 90% CI: 1.17, 1.01–1.36) and Cmax by 15% (LS
means ratio, 90% CI: 1.15, 0.97–1.35) after
coadministration of TMC114/r (Table 2).
Systemic exposure to low-dose RTV coadministered
with TMC114 was decreased in the presence of EFV.
Based on the LS means ratio, there was a decrease of
28% in RTV AUC12h (LS means ratio, 90% CI: 0.72,
0.61–0.84), a decrease of 32% in RTV Cmax (LS means
ratio, 90% CI: 0.68, 0.58–0.81) and a decrease of 40%
in RTV Cmin (LS means ratio, 90% CI: 0.60, 0.47–0.77)
in the presence of EFV.
Antiviral Therapy 12:4
A
Plasma concentration of
TMC114, ng/ml
Results
Figure 1. Mean plasma concentration–time profiles of
TMC114 and EFV
3,500
3,000
2,500
2,000
1,500
1,000
without EFV
with EFV
500
0
0
2
4
6
8
10
12
10
12
Scheduled time, h
B
Plasma concentration of
EFV, ng/ml
performed using linear mixed effect modelling. The
least square (LS) means ratio and 90% confidence
intervals (CI) around the LS means ratio were reported
with treatment of TMC114/r alone or treatment of
EFV alone as reference. The nonparametric t-test
(Koch) was used for tmax. No statistical analysis was
performed for other pharmacokinetic parameters.
5,000
4,000
3,000
2,000
without TMC114/r
with TCMC114/r
1,000
0
0
2
4
6
8
Scheduled time, h
(A) TMC114 administered as TMC114/r 300/100 mg twice daily without or with
steady-state concentrations of efavirenz (EFV) 600 mg daily on day 7 of session
1 and day 17 of session 2, respectively. (B) EFV administered as 600 mg daily
without or with TMC114/r 300/100 mg twice daily on day 10 and 17 of session
2, respectively. TMC114/r, darunavir with low-dose ritonavir.
Safety and tolerability
All 12 volunteers reported at least one AE during the
trial. Of all AEs reported, 63%, 34% and 3% were
classified by the investigator as mild, moderate and
severe, respectively. All severe events were reported
during treatment with EFV. The most commonly
reported AEs during the entire trial were nervous
system disorders (12/12 volunteers), general disorders
(which included fatigue, feeling hot, symptoms associated with excess alcohol consumption and loin pain;
9/12), gastrointestinal disorders (9/12) and psychiatric
disorders (9/12). Nine volunteers experienced nervous
system disorder-related AEs during combined treatment
with EFV and TMC114/r, with headache, dizziness,
somnolence and disturbance in attention occurring in
4/12, 7/12, 7/12 and 3/12 volunteers, respectively.
Gastrointestinal disorders occurred in 9/12 volunteers
during combined treatment with EFV and TMC114/r.
Of these, three volunteers (3/12) each suffered from
diarrhoea and vomiting and five volunteers (5/12)
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VJ Sekar et al.
Table 1. Statistical evaluation of the pharmacokinetic characteristics of TMC114 administered as TMC114/r 300/100 mg
twice daily with or without coadministration of EFV 600 mg
once daily
LS means
Parameter
TMC114/r
TMC114/r
+ EFV
Ratio
90% CI
n
tmax, h
Cmin, ng/ml
Cmax, ng/ml
AUC12h, ng•h/ml
12
0.75 [0.0–2.0]
1772 ±708
3,460 ±943
28,865 ±8,360
12
0.5 [0.5–3.0]
1,250 ±511
2,998 ±938
25,483 ±7,844
—
0.69
0.85
0.87
—
0.54–0.87
0.72–1.00
0.75–1.01
tmax value is median (range); all other values are mean ±SD. AUC, area under
plasma concentration–time curve; Cmax, maximum plasma concentration; Cmin,
minimum plasma concentration; CI, confidence interval; EFV, efavirenz; LS,
least square; tmax, time to maximum plasma concentration; TMC114/r, darunavir
with low-dose ritonavir.
Table 2. Statistical evaluation of the pharmacokinetic
characteristics of EFV 600 mg once daily with or without
coadministration of TMC114/r 300/100 mg twice daily
Session 2
Parameter
Day 10
EFV
LS means
Day 17
EFV + TMC114/r Ratio 90% CI
n
tmax, h
Cmin, ng/ml
Cmax, ng/ml
AUC24h, ng•h/ml
12
4.0 [2.0–5.0]
1,647 ±1,078
4,595 ±1,480
61,800 ±30,350
12
4.0 [3.0–5.0]
1,989 ±1,621
5,297 ±1,889
76,429 ±45,527
—
1.17
1.15
1.21
—
1.01–1.36
0.97–1.35
1.08–1.36
tmax value is median (range); all other values are mean ±SD. AUC, area under
plasma concentration–time curve; Cmax, maximum plasma concentration; Cmin,
minimum plasma concentration; CI, confidence interval; EFV, efavirenz; LS,
least square; tmax, time to maximum plasma concentration; TMC114/r, darunavir
with low-dose ritonavir.
reported nausea. Three volunteers reported rash during
treatment with EFV alone or during combined treatment with EFV and TMC114/r. No serious AEs or AEs
leading to withdrawal were reported in this trial. In this
study, EFV was administered in the presence of food;
according to the US package insert for Sustiva (ie EFV),
taking EFV with food increases EFV concentrations
and may increase the frequency of adverse events.
Most observed laboratory abnormalities were grade 1
in severity. Treatment-emergent grade 2 increases in
cholesterol were observed during the following treatment phases: TMC114/r (2/12), EFV alone (3/12) and
combined EFV and TMC114/r treatment (4/12). No
grade 4 abnormalities were reported. One volunteer
reported a treatment-emergent grade 3 elevation in
cholesterol during combined EFV and TMC114/r treatment. One case of treatment-emergent grade 2 increase
in alanine aminotransferase (ALT) was reported during
combined EFV and TMC114/r treatment. No grade 3 or
512
4 elevations of ALT were observed and no abnormalities
of aspartate aminotransferase were noted throughout
the study. No abnormalities in vital signs or electrocardiograms leading to AEs were observed.
Discussion
The efficacy and safety of an antiretroviral regimen
containing both TMC114/r and EFV may depend on
the overall effect of the various pharmacokinetic interactions that may occur in the shared metabolic pathways. It is known that drug interactions mediated
through the CYP3A4 isozyme can be clinically significant. EFV is an inducer of CYP3A4 and increases the
rate of biotransformation of coadministered drugs that
are CYP3A4 substrates [20,21]. EFV is a mixed
inhibitor/inducer of other cytochrome isozymes, such
as CYP2B6 and CYP3A. RTV inhibits CYP2B6 and is
a potent inhibitor of CYP3A4 and, to a lesser extent,
CYP2D6 [22–25]. RTV is also an inducer of certain
other CYP isozymes [23]. TMC114 is both a substrate
and an inhibitor of CYP3A4. Given the complex range
of interactions of these three drugs with the P450
system, it is important to examine the effect of their
coadministration in a clinical setting.
In the ongoing POWER 1 (TMC114-C213) and
POWER 2 (TMC114-C202) randomized controlled
trials, designed to evaluate the efficacy and safety of
TMC114/r in treatment-experienced HIV patients,
four TMC114/r doses (400/100 mg once daily,
800/100 mg once daily, 400/100 mg twice daily and
600/100 mg twice daily) were compared with control PI
regimens. An optimized background regimen consisting
of NRTIs with or without enfuvirtide was used in each
treatment arm. In pharmacokinetic analyses, there was
no correlation with efficacy and TMC114 exposure at
the recommended dose (600/100 mg twice daily),
however, TMC114 fold change was a strong predictor
of response [26,27]. EFV was not permitted in the
POWER 1 or 2 studies as eligible subjects were required
to be NNRTI-experienced; nevertheless, based on these
analyses, the 13% decrease in TMC114 exposure due
to EFV coadministration observed in this present study
is not likely to be clinically relevant. The pharmacokinetic and pharmacodynamic relationships observed in
the POWER studies support the selection of the
TMC114/r 600/100 mg twice daily dose for the treatment of HIV-1 infected patients with prior treatment
experience [25].
In this study, coadministration of EFV with
TMC114/r resulted in a 21% increase in EFV exposure
(AUC24h) and a 13% decrease in TMC114 exposure
(AUC12h). When TMC114/r and EFV were administered concomitantly, Cmin of TMC114 was decreased
by 31%. However, the mean TMC114 Cmin in the
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PK interaction of TMC114/r and efavirenz
presence of EFV was 20-fold and sixfold greater than
wild-type IC50 and IC90, respectively [17]. Concomitant
administration of TMC114 300 mg with RTV 100 mg
twice daily and EFV 600 mg once daily resulted in a
decreased exposure to TMC114. Exposure to EFV was
increased when administered with TMC114/r; the clinical significance of these changes has not been established. Exposure (AUC) to TMC114 has been found to
increase less than dose proportionally. In HIV-infected
patients receiving TMC114/r doses of 400/100 mg
twice daily or 600/100 mg twice daily regimens, a
considerable overlap in the exposure to TMC114 was
obtained with these two dosing regimens. The 50%
increase in dose between the 400/100 mg twice daily
and 600/100 mg twice daily regimens resulted in only a
29% increase in median TMC114 exposure [26]. On
this basis, the results of this study conducted with the
TMC114/r 300/100 mg twice daily regimen is considered applicable to subjects receiving the recommended
600/100 mg twice daily dosing regimen.
In conclusion, combinations of TMC114/r and EFV
should be used with caution. Given the need to
combine active antiretroviral drugs in the treatment of
HIV infection, the coadministration of NNRTIs and
TMC114/r is permitted and is currently being evaluated in an ongoing Phase III clinical trial in treatmentexperienced patients (TMC114-C214 or TITAN).
4.
5.
6.
7.
8.
9.
10.
Acknowledgements
Medical writing services were provided by Fiona
Fernando of Gardiner-Caldwell Communications
(GCC), Macclesfield, UK.
This study was financially supported by Tibotec
Pharmaceuticals Inc.
Conflict of interest
11.
12.
13.
All authors are employees of Tibotec.
14.
Disclosure
Some of the data shown in this article have previously
been presented as a poster presentation at the 7th
International Workshop on Clinical Pharmacology of
HIV Therapy, 20–22 April 2006, Lisbon, Portugal;
poster 55.
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