Download Pharmacokinetic profile and safety of 150 mg of

J Antimicrob Chemother
doi:10.1093/jac/dkt006
Pharmacokinetic profile and safety of 150 mg of maraviroc dosed with
800/100 mg of darunavir/ritonavir all once daily, with and without
nucleoside analogues, in HIV-infected subjects
Borja Mora-Peris1*, Adam Croucher2, Laura J. Else3, Jaime H. Vera1,2, Saye Khoo3, George Scullard2,
David Back3 and Alan Winston1,2
1
Department of Medicine, Faculty of Medicine, Imperial College London, St Mary’s Hospital Campus, Norfolk Place, London W2 1PG, UK;
2
Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust, St Mary’s Hospital, Praed Street, London
W2 1NY, UK; 3Department of Molecular & Clinical Pharmacology, University of Liverpool, Liverpool, UK
*Corresponding author. Clinical Trials, Winston Churchill Wing, St Mary’s Hospital, Imperial College London, Praed Street, London W2 1NY, UK.
Tel/Fax: +44-203-312-6738/6123; E-mail: [email protected]
Received 8 October 2012; returned 22 November 2012; revised 14 December 2012; accepted 31 December 2012
Background: Once-daily nucleoside-sparing combination antiretroviral therapy regimens are attractive options
for the treatment of HIV infection. However, the pharmacokinetic profiles of such regimens are often not
established.
Methods: HIV-infected subjects receiving 245/200 mg of tenofovir/emtricitabine plus 800/100 mg of darunavir/
ritonavir once daily with plasma HIV RNA ,50 copies/mL were eligible. On day 1 (period 1), 150 mg of maraviroc daily was added and on day 11 (period 2), tenofovir/emtricitabine discontinued. At steady-state (days 10
and 20), intensive pharmacokinetic sampling was undertaken. We assessed (i) the number of subjects with
trough (Ctrough) and average (Cavg) maraviroc concentrations ,25 and ,75 ng/mL, respectively; (ii) geometric
mean (GM) ratios for pharmacokinetic parameters for period 2 versus period 1; and (iii) factors associated
with total maraviroc exposure.
Results: Eleven subjects completed the study procedures (mean age 49 years; range 35 –59 years). In three
subjects, maraviroc Ctrough and Cavg were ,25 and ,75 ng/mL, respectively (Cavg, 68 ng/mL and Ctrough, 14
and 21 ng/mL). Although not statistically significant, a trend was observed towards lower maraviroc, darunavir
and ritonavir concentrations in period 2 versus period 1; total maraviroc exposure was 3579 ng. h/mL (95% CI:
2983 –4294) and 2996 ng. h/mL (95% CI: 2374–3782) in periods 1 and 2, respectively, and the GM ratio was
0.84 (95% CI: 0.67 –1.05). Only total ritonavir exposure was significantly associated with total maraviroc exposure (P ¼ 0.049; 95% CI: 0.01– 0.91). No clinical safety concerns were observed.
Conclusions: Within this novel nucleoside-sparing regimen, maraviroc exposure is dependent on ritonavir
exposure, which was slightly reduced in the absence of tenofovir/emtricitabine.
Keywords: antiretroviral therapy, HIV, HIV antiviral pharmacology, nucleoside sparing
Introduction
Modern combination antiretroviral therapy (cART) for HIV infection is one of the major medical advances of recent years. By
preventing HIV disease progression, cART has transformed HIV
infection into a chronic manageable medical condition.1 – 3
Despite this success, antiretroviral therapy is lifelong and strategies are urgently needed to overcome the ensuing toxicities of
such long-term therapy. One such strategy is nucleoside-sparing
antiretroviral therapy, where the long-term side effects of nucleoside reverse transcriptase inhibitors may be avoided.4 – 6
However, often the pharmacokinetic profiles of such regimens
are not well described.
An attractive, potential nucleoside-sparing cART regimen is
maraviroc, darunavir and ritonavir, all dosed once daily. Maraviroc is a CCR5 receptor antagonist approved for use in the treatment of HIV-1.7,8 It is metabolized in the liver by the CYP3A4
pathway.9,10 Darunavir, an HIV-protease inhibitor, is also primarily metabolized in the liver by the CYP3A4 isoenzyme. The metabolism of both of these agents is inhibited by ritonavir, a CYP3A
inhibitor,11 increasing their plasma exposure. For example, the
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JAC
Maraviroc/darunavir pharmacokinetic study
total and maximum plasma exposure of maraviroc are increased
by 4.1- and 2.3-fold, respectively, when maraviroc is dosed with
600/100 mg of darunavir/ritonavir twice daily compared with
maraviroc alone.12 This raises the possibility of utilizing a oncedaily maraviroc dosing schedule in combination with a ritonavirboosted protease inhibitor. Clinical data support this approach. In
highly treatment-experienced HIV-infected subjects receiving
either once- or twice-daily maraviroc (150 mg) in combination
with boosted protease inhibitors, similar virological responses
have been described with both maraviroc doses.8,13
The objective of this study was to assess the safety, tolerability and steady-state pharmacokinetic profile of 800/100/150 mg
of darunavir/ritonavir/maraviroc all dosed once daily, with and
without 245/200 mg of tenofovir/emtricitabine, in HIV-infected
subjects receiving stable antiretroviral therapy.
Methods
Study design
This prospective pharmacokinetic study was conducted at Imperial
College Healthcare NHS Trust (St Mary’s Hospital, London, UK) between
October 2011 and January 2012. Adult subjects on stable once-daily
antiretroviral therapy comprising 245 mg of tenofovir, 200 mg of emtricitabine, 800 mg of darunavir and 100 mg of ritonavir were eligible to participate. Exclusion criteria included current alcohol abuse or drug
dependence, positive urine for drug of abuse at screening (InstallertTM ;
Innovacon Inc., San Diego, CA, USA), pregnancy, active opportunistic infection or significant comorbidities, such as hepatitis B or C infection,
and the use of concomitant medication with known interaction potential.
Additional inclusion criteria included the following: CCR5-tropic HIV based
on a genotypic tropism assay [by sequencing of the V3 region of the env
and submission to the Geno2pheno algorithm (clonal analysis, 5.75%
false positive rate cut-off)] from either a stored plasma sample, where
available, or fresh plasma; plasma HIV RNA ,50 copies/mL (Quantiplex
assayTM ; Bayer, Emeryville, CA, USA) at screening and on at least one
other occasion over the last 3 months; normal screening laboratory
testing parameters; and a body mass index between 18 and 32 kg/m2.
This study was registered in the European Clinical Trials Database
(EudraCT number 2009-014924-42) and local ethical approval was
granted prior to recruiting participants. All patients were required to
sign an informed consent prior to entering screening.
Study procedures
During study period 1 (days 1 –10), 150 mg of maraviroc once daily was
added to the current cART and in study period 2 (day 11– 20), tenofovir/
emtricitabine was discontinued (Figure S1, available as Supplementary
data at JAC Online). Treatment compliance was assessed on days 10
and 20 by study staff through a pill count. The study treatment ceased
and subjects recommenced their pre-study, usual antiretroviral regimen
on day 21. A urine drug screen for illegal substances, CD4+ lymphocyte
count, haematology and chemistry panels were undertaken throughout
the study period. HIV RNA was measured at screening, baseline, day
10, day 20 and the follow-up visit at days 30–35.
Pharmacokinetic analysis
Intensive pharmacokinetic sampling was performed on days 10 and
20 when steady-state had been achieved. Blood samples for darunavir,
ritonavir and maraviroc were collected 10 min prior to dosing and 0.5,
1, 2, 3, 4, 6, 8, 10, 12 and 24 h post-dosing. Dosing took place at a fed
state after a standardized breakfast. Darunavir, ritonavir and maraviroc
concentrations were determined using HPLC– tandem mass spectrometry as previously described.14 The lower limits of quantification
for darunavir, ritonavir and maraviroc were 16, 5 and 5 ng/mL, respectively. Inter- and intra-assay precision did not exceed 10% for any
compound.
Statistical analysis
Pharmacokinetic parameters were calculated using non-compartmental
methods (WinNonlin; Pharsight Corporation, Mountain View, CA, USA).
The 95% CIs were constructed for the ratio of geometric means (GMs)
of the AUC (AUC0 – 24), average plasma concentration (Cavg; defined as
the AUC0 – 24/24), maximum plasma concentration (defined as the
maximum observed concentration, Cmax) and trough plasma concentration (defined as the concentration at 24 h after the observed dose,
Ctrough) for each of maraviroc, darunavir and ritonavir for both study
periods.
All statistical calculations were performed and analysed using SPSS
(version 19.0; SPSS Inc., Chicago, IL, USA). Within-subject changes in
the assessed pharmacokinetic parameters between days 10 and 20
were evaluated by assessment of GM ratios (GMR) and the corresponding
95% CIs. The CIs were determined using logarithms of the individual GM
values; the calculated values were then expressed as linear values.
Changes in the pharmacokinetic parameters were considered significant
when the 95% CI did not cross one. Interpatient variability in the
pharmacokinetic parameters was expressed as a coefficient of variation
(CV) [(standard deviation/mean)×100]. The number of subjects with
maraviroc Ctrough and Cavg ,25 and ,75 ng/mL (concentrations previously
associated with near-maximal virological responses9,15) were assessed, as
was the number of individuals with maraviroc Cmax .1000 ng/mL (concentration associated with increased risk for postural hypotension16,17).
Subject characteristics and laboratory parameters were described.
Associations between total maraviroc plasma exposure (log10 transformed) and both patient characteristics and total ritonavir and
darunavir exposure were investigated using linear regression modelling.
The CIs were then expressed as linear values. All univariate associations
with P values ,0.1 were included in the multivariate analyses, where
values ,0.05 were considered statistically significant.
Results
Patient characteristics and drug tolerability
Of 19 subjects screened, 13 were enrolled. The presence of
CXCR4 HIV strains was the predominant reason for subjects
failing study screening procedures. Of the 13 enrolled subjects,
1 subject underwent early termination due to poor compliance
with the study therapy and another subject discontinued due
to a concurrent seasonal viral illness, leaving 11 individuals
who completed both study periods (Figure S1). The patients’
baseline characteristics are described in Table 1. The study medications were well tolerated and no safety or laboratory concerns
were observed. All 11 patients reported 100% adherence to the
therapy. During the study and follow-up periods, the plasma HIV
RNA of all patients remained undetectable.
Pharmacokinetic parameters over study periods
The pharmacokinetic parameters for maraviroc, darunavir and ritonavir are shown in Table 2. Three separate individuals had maraviroc concentrations (Cavg or Ctrough) below the levels associated
with near-maximal efficacy as follows: one individual had
a maraviroc Cavg ,75 ng/mL in study period 2 (68 ng/mL)
1349
Mora-Peris et al.
(Figure 1a), one subject had a maraviroc Ctrough ,25 ng/mL in
period 1 (14 ng/mL) and another in period 2 (21 ng/mL)
(Figure 1b). No individual had a documented maraviroc Cmax
.1000 ng/mL.
Table 1. Patient demographics and clinical characteristics
Factors associated with maraviroc plasma exposure
Parameter
Number of participants
Age (years), mean (SD)
Male, n (%)
11
47.9 (8.8)
9 (82)
Ethnicity, n (%)
Caucasian
black
Baseline CD4+ count (cells/mL), mean (SD)
HIV RNA ,50 copies/mL for .3 months, n (%)
8 (73)
3 (27)
558 (271)
11 (100)
HIV subtype, n (%)
not available
B
D
A/D
Current smoker, n (%)
Antiretroviral therapy of emtricitabine/
tenofovir+darunavir/ritonavir at screening, n (%)
Duration of darunavir/ritonavir therapy prior to study
entry (months), mean (SD)
Patients on first-line therapy or having started therapy
with a protease inhibitor as third agent, n (%)
Time under virological success (months), median (IQR)
Although no statistically significant differences in pharmacokinetic parameters were observed between periods 2 and 1 for
maraviroc, darunavir or ritonavir, slight reductions in Ctrough,
Cavg and AUC0 – 24 were observed in period 2 compared with
period 1.
4 (36.4)
5 (45.6)
1 (9)
1 (9)
3 (27)
11 (100)
16.4 (14.7)
9 (81.8)
39 (65)
On day 20, although several factors were associated with total
maraviroc exposure in a univariate model, in a multivariate analysis only total ritonavir exposure was significantly associated
with total maraviroc exposure (P ¼ 0.049; 95% CI: 0.01 –0.91)
(Table S1, available as Supplementary data at JAC Online).
Discussion
In this study assessing a nucleoside-sparing antiretroviral
regimen comprising 800/100/150 mg of darunavir/ritonavir/maraviroc all dosed once daily, no short-term efficacy or safety concerns were observed. Interestingly, we observed small reductions
in maraviroc, darunavir and ritonavir total plasma exposure
when dosed without tenofovir/emtricitabine, although these
changes were not statistically significant.
During the study period, plasma maraviroc concentrations
were below concentrations associated with near-maximal efficacy (75 and 25 ng/mL for Cavg and Ctrough, respectively9,15) in
three subjects (Ctrough of 14 ng/mL in one subject in period 1
and 21 ng/mL in one subject in period 2 and Cavg of 68 ng/mL
in one subject in period 2). Despite this, no evidence of loss of
HIV virological control was observed, with several possible explanations for this. Firstly, recruited subjects had no evidence of HIV
strains harbouring drug resistance-associated mutations and
Table 2. Pharmacokinetic parameters results for maraviroc, darunavir and ritonavir (n¼11)
Day 10, GM
value (95% CI)
Maraviroc
Ctrough (ng/mL)
Cmax (ng/mL)
Cavg (ng/mL)
AUC0 – 24 (ng . h/mL)
t12 (h)
Darunavir
Ctrough (ng/mL)
Cmax (ng/mL)
Cavg (ng/mL)
AUC0 – 24 (ng . h/mL)
t12 (h)
Ritonavir
Ctrough (ng/mL)
Cmax (ng/mL)
Cavg (ng/mL)
AUC0 – 24 (ng . h/mL)
t12 (h)
1350
48.8 (32.8–72.6)
415 (341–504)
149 (124–179)
3579 (2983– 4294)
9.6 (6.9–13.5)
1465 (906–2368)
5861 (4692– 7321)
2799 (2271– 3450)
67177 (54506– 82794)
19.2 (10.7–34.6)
47.6 (33.4–67.8)
409 (311–537)
176 (135–231)
4235 (3236– 5541)
6.6 (5.2–8.5)
Day 20, GM
CV%
51
27
26
26
50
59
30
30
30
106
46
35
31
31
33
value (95% CI)
44.9 (35.7– 56.3)
413 (311– 547)
125 (99 –158)
2996 (2374–3782)
10.9 (8.6 –13.9)
1563 (1166–2094)
5534 (4431–6912)
2542 (1998–3234)
61002 (47 941–77621)
20.7 (14.6– 29.4)
49.6 (34.2– 71.9)
353 (271– 462)
161 (128– 204)
3873 (3064–4896)
7.7 (5.4 –10.9)
CV%
GMR day 20/day 10 (95% CI)
30
42
33
33
38
0.92 (0.55–1.54)
0.99 (0.79–1.25)
0.84 (0.67–1.05)
0.84 (0.67–1.05)
1.13 (0.76–1.69)
46
37
37
37
64
1.07 (0.63–1.81)
0.94 (0.79–1.13)
0.91 (0.78–1.06)
0.91 (0.78–1.06)
1.09 (0.48–2.44)
42
37
31
31
68
1.04 (0.62–1.75)
0.86 (0.70–1.07)
0.91 (0.81–1.03)
0.91 (0.81–1.03)
1.16 (0.77–1.75)
JAC
Maraviroc/darunavir pharmacokinetic study
MVC Cavg
MVC Cavg (ng/mL)
(a)
250
225
200
175
150
125
100
75
50
25
0
GMR day 20/day 10 (95% CI) : 0.84 (0.67–1.05)
Cavg=75 ng/mL
#
Day 10
Day 20
Study periods
MVC Ctrough (ng/mL)
(b) 150
MVC Ctrough
GMR day 20/day 10 (95% CI): 0.92 (0.55–1.54)
125
100
75
50
25
** C
*
trough=25
ng/mL
0
Day 10
Day 20
Study periods
Figure 1. (a) Maraviroc average plasma concentration levels (MVC Cavg)
during periods 1 and 2 of the study. Filled triangles, individual subjects;
#, subject 2. (b) Maraviroc trough plasma concentration levels (MVC
Ctrough) during periods 1 and 2 of the study. Filled triangles, individual
subjects; *, subject 10; **, subject 6.
remained on darunavir/ritonavir throughout the study period.
Darunavir/ritonavir alone is likely to provide sufficient antiretroviral activity to maintain suppression of HIV viraemia in such subjects.18,19 Furthermore, within the short study time frame,
rebound of viraemia may not have been observed. Secondly,
the proposed optimal lower maraviroc Ctrough is ≥24-fold higher
than the serum-adjusted EC90 of 0.57 ng/mL (0.06 –10.7),
based on laboratory testing from 43 primary HIV-1 clinical isolates;20 hence, lower concentrations of maraviroc are likely to
provide antiretroviral activity. Additionally, variability in maraviroc
Ctrough in our study was generally high, which may limit the clinical relevance of this pharmacokinetic parameter.
Pharmacokinetic data from a cohort study assessing differing
maraviroc dosing schedules being utilized in clinical practice,
reported similar maraviroc Ctrough exposure of 43 ng/mL (IQR
35 –55) to that seen in our study in the group receiving the
same antiretroviral regimen.21 Within this cohort, when higher
doses of maraviroc were utilized in clinical practice, such as
300 mg once daily, as expected, greater plasma exposure of
maraviroc was observed. Although no clinical cases of toxicity
(postural hypotension) were observed with higher doses of
maraviroc in this cohort study, 9% (6/66) of subjects had a
peak maraviroc concentration of .1000 ng/mL, which may be
associated with an increased risk for postural hypotension. Furthermore, due to sparse pharmacokinetic sampling, this may
be an under-representation of the true peak concentrations, as
sampling near the time of maximal exposure may have been
missed in many subjects. However, we did not observe any
peak maraviroc concentration .1000 ng/mL and can be confident not to have missed maximum plasma exposure in our
study, as all subjects completed all of the intensive pharmacokinetic measurements as per the study protocol. Similar studies
have been carried out to assess the combination of darunavir/ritonavir and maraviroc twice daily, which showed good tolerability and favourable pharmacokinetic profiles.22
Although our study findings suggest that with the dosing
regimen we studied, maximum maraviroc plasma exposure is
unlikely to reach concentrations associated with risk for postural
hypotension, on the converse, minimum exposure of maraviroc is
near the lower proposed therapeutic threshold and studies
assessing the virological efficacy of this regimen are required.
Indeed, such a study is underway. The MODERN study is assessing 150/800/100 mg of maraviroc/darunavir/ritonavir alone, all
once daily, in a prospective, randomized, double-blind study, as
a therapeutic option for therapy-naive HIV-infected individuals.23
Here, the clinical efficacy of the novel regimen we have studied
will be tested against standard antiretroviral therapy including
nucleoside analogues. Examining this novel regimen in this challenging treatment scenario, namely assessing virological response in subjects commencing antiretroviral therapy for the
first time, allows one of the ultimate tests of efficacy in HIV
therapeutics.
Interestingly, general reductions in the total plasma exposure
of all drugs were observed on discontinuation of tenofovir/emtricitabine, although these reductions were not of statistical significance. A previous study has reported small reductions in
darunavir exposure24 on discontinuation of tenofovir/emtricitabine, but no change in ritonavir exposure. With regard to other
HIV-protease inhibitors, no changes in saquinavir concentrations
are reported when administered with or without tenofovir25 and
reductions in atazanavir exposure have been reported when
administered with tenofovir,26,27 although the clinical relevance
of this interaction remains disputed.28 To our knowledge, no
interactions between emtricitabine itself and other antiretrovirals
have been reported.29,30 Maraviroc is a substrate of the ABCB1
(P-glycoprotein) efflux transporter and the CYP3A isoenzyme.9,10
Tenofovir does not undergo CYP3A or hepatic metabolism31 and,
historically, no significant pharmacokinetic interactions with
maraviroc have been described.32 We believe the reductions in
darunavir and maraviroc exposure we observed are likely
related to the slight reduction in ritonavir exposure observed in
period 2. However, the mechanism underpinning the slight decrease in ritonavir exposure during this study period remains
elusive. Regarding other factors that could affect the metabolism
of maraviroc, the lack of genotype testing in our study made it
impossible to assess the correlation of OATP1B1 polymorphisms
observed in vitro with plasma concentrations of maraviroc as a
substrate of this transporter.10
In this study, maraviroc concentrations in the CSF were not
assessed and this could be critical in the activity of maraviroc
against CCR5-using strains, common in the brain. Recent
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Mora-Peris et al.
studies have evaluated the concentration of unbound maraviroc
in plasma as a research tool to estimate penetration in the
CNS.33 However, total concentrations were measured in this
study and no estimation of the concentration in the CSF is
possible.
Other studies have reported higher maraviroc concentrations
at trough in subjects of black ethnicity.21 Such a trend was also
present in our study but there was a lack of statistical significance of this association due to the small number of subjects,
especially those of black ethnicity.
With an ageing HIV-infected population and the need for lifelong effective antiretroviral therapy, novel, once-daily, antiretroviral treatment strategies, avoiding the long-term toxicities
associated with nucleoside analogues, are urgently required. Unfortunately, studies in recent years have reported disappointing
efficacy results when utilizing such nucleoside-sparing treatment
regimens.34 – 36 This lack of efficacy may for some regimens be
associated with pharmacokinetic concerns,37 highlighting the
need for the detailed pharmacokinetic profiles of such regimens
to be determined in the population where such regimens will be
utilized. Our results, describing the pharmacokinetic profile of
800/100/150 mg of darunavir/ritonavir/maraviroc dosed once
daily without nucleoside analogues in HIV-infected subjects,
add to the growing knowledge in this field, with the results of
clinical efficacy studies awaited.
Acknowledgements
We are grateful to the NIHR Biomedical Facility at Imperial College
London for infrastructure support.
We are grateful to Simon Portsmouth (Pfizer) and Manoli Vourvahis
(Pfizer) for their assistance in interpreting some of the pharmacokinetic
results.
We would like to thank all the study participants, the nursing and
pharmacy staff and the Clinical Trials Centre, Imperial College London
(St Mary’s Campus), UK (Ken Legg, Ngaire Latch, Kanta Jhalli, Ling-Jun
Chen, Scott Mullaney, Siobhan McKenna, Nadia Naous and Rosy Weston).
References
1 Antiretroviral Therapy Cohort Collaboration. Life expectancy of
individuals on combination antiretroviral therapy in high-income
countries: a collaborative analysis of 14 cohort studies. Lancet 2008;
372: 293–9.
2 Egger M, May M, Chene G et al. Prognosis of HIV-1-infected patients
starting highly active antiretroviral therapy: a collaborative analysis of
prospective studies. Lancet 2002; 360: 119–29.
3 Egger M, Hirschel B, Francioli P et al. Impact of new antiretroviral
combination therapies in HIV infected patients in Switzerland:
prospective multicentre study. Swiss HIV Cohort Study. BMJ 1997; 315:
1194– 9.
4 Negredo E, Miro O, Rodriguez-Santiago B et al. Improvement of
mitochondrial toxicity in patients receiving a nucleoside reversetranscriptase inhibitor-sparing strategy: results from the Multicenter
Study with Nevirapine and Kaletra (MULTINEKA). Clin Infect Dis 2009;
49: 892–900.
5 Tebas P, Zhang J, Hafner R et al. Peripheral and visceral fat changes
following a treatment switch to a non-thymidine analogue or a
nucleoside-sparing regimen in HIV-infected subjects with peripheral
lipoatrophy: results of ACTG A5110. J Antimicrob Chemother 2009; 63:
998–1005.
6 Williams I, Churchill D, Anderson J et al. British HIV Association
guidelines for the treatment of HIV-1-positive adults with antiretroviral
therapy 2012. HIV Med 2012; 13 Suppl 2: 1 – 6.
7 Vandekerckhove L, Verhofstede C, Vogelaers D. Maraviroc: perspectives
for use in antiretroviral-naive HIV-1-infected patients. J Antimicrob
Chemother 2009; 63: 1087 –96.
8 Gulick RM, Lalezari J, Goodrich J et al. Maraviroc for previously treated
patients with R5 HIV-1 infection. N Engl J Med 2008; 359: 1429– 41.
9 Abel S, Back DJ, Vourvahis M. Maraviroc: pharmacokinetics and drug
interactions. Antivir Ther 2009; 14: 607–18.
10 Siccardi M, D’Avolio A, Nozza S et al. Maraviroc is a substrate for
OATP1B1 in vitro and maraviroc plasma concentrations are influenced
by SLCO1B1 521 T.C polymorphism. Pharmacogenet Genomics 2010;
20: 759–65.
11 Kumar GN, Rodrigues D, Buko AM et al. Cytochrome P450-mediated
metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in
human liver microsomes. J Pharmacol Exp Ther 1996; 277: 423–31.
The study was funded through an investigator grant awarded to A. W. by
Pfizer.
12 Abel S. An open, randomised, 2-way crossover study to investigate
the effect of darunavir/ritonavir on the pharmacokinetics of maraviroc
in healthy subjects. In: Abstracts of the Eighth International Workshop
on Clinical Pharmacology of HIV Therapy, Budapest, April 2007. Abstract
55.
Transparency declarations
13 Hardy WD, Gulick RM, Mayer H et al. Two-year safety and virologic
efficacy of maraviroc in treatment-experienced patients with
CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1
and 2. J Acquir Immune Defic Syndr 2010; 55: 558– 64.
Funding
D. B. has received honoraria or research grants from Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Roche and
ViiV. A. W. has received honoraria or research grants from or been a consultant or investigator in clinical trials sponsored by Abbott, Boehringer
Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline,
Janssen-Cilag, Roche, Pfizer and ViiV Healthcare. All other authors:
none to declare.
Supplementary data
Figure S1 and Table S1 are available as Supplementary data at JAC Online
(http://jac.oxfordjournals.org/).
1352
14 Else L, Watson V, Tjia J et al. Validation of a rapid and sensitive
high-performance liquid chromatography-tandem mass spectrometry
(HPLC-MS/MS) assay for the simultaneous determination of existing and
new antiretroviral compounds. J Chromatogr B Analyt Technol Biomed
Life Sci 2010; 878: 1455– 65.
15 Taylor S, Dufty N, Watson J. MVC 300 mg once daily+DRV/RTV 800/
100 mg once daily provides MVC trough concentrations comparable to
trough concentrations in HIV-1 patients taking MVC 300 mg twice
daily+TVD: implications for Phase 3 studies. In: Eighteenth Conference
on Retroviruses and Opportunistic Infections, Boston, MA, 2011. Poster
636. Foundation for Retrovirology and Human Health, Alexandria, VA,
USA.
JAC
Maraviroc/darunavir pharmacokinetic study
16 Abel S, van der Ryst E, Rosario MC et al. Assessment of the
pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5
antagonist, in healthy volunteers. Br J Clin Pharmacol 2008; 65 Suppl 1:
5 –18.
17 Weatherley B, Vourvahis M, McFadyen L. Modeling of maraviroc
pharmacokinetics in the presence of atazanavir/ritonavir in healthy
volunteers and HIV-1-infected patients. In: Abstracts of the Twelfth
International Workshop on Clinical Pharmacology of HIV Therapy, Miami,
FL, 2011. Abstract P_05.
18 Arribas JR, Clumeck N, Nelson M et al. The MONET trial: week 144
analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy
versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for
patients with viral load ,50 HIV-1 RNA copies/mL at baseline. HIV Med
2012; 13: 398–405.
19 Valantin MA, Lambert-Niclot S, Flandre P et al. Long-term efficacy of
darunavir/ritonavir monotherapy in patients with HIV-1 viral
suppression: week 96 results from the MONOI ANRS 136 study.
J Antimicrob Chemother 2012; 67: 691–5.
20 EMEA. CELSENTRI Scientific Discussion. 2007. http://www.ema.europa.
eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/00
0811/WC500022194.pdf (14 January 2013, date last accessed).
immunodeficiency
virus-infected
Chemother 2004; 48: 2091 –6.
patients.
Antimicrob
Agents
27 Kaul S, Bassi K, Damle B. Pharmacokinetic evaluation of the
combination of atazanavir, enteric coated didanosine and tenofovir
disoproxil fumarate for a once daily antiretroviral regimen. In: Abstracts
of the Forty-third Interscience Conference on Antimicrobial Agents and
Chemotherapy, Chicago, IL, 2003. Abstract A-1616. American Society
for Microbiology, Washington, DC, USA.
28 von Hentig N, Dauer B, Haberl A et al. Tenofovir comedication does
not impair the steady-state pharmacokinetics of ritonavir-boosted
atazanavir in HIV-1-infected adults. Eur J Clin Pharmacol 2007; 63:
935–40.
29 Parks DA, Jennings HC, Taylor CW et al. Pharmacokinetics of
once-daily tenofovir, emtricitabine, ritonavir and fosamprenavir in
HIV-infected subjects. AIDS 2007; 21: 1373– 5.
30 Zong J, Chittick GE, Wang LH et al. Pharmacokinetic evaluation of
emtricitabine in combination with other nucleoside antivirals in healthy
volunteers. J Clin Pharmacol 2007; 47: 877–89.
31 Gilead. VIREAD Full Prescribing Information. 2012. http://www.gilead.
com/pdf/viread_pi.pdf (14 January 2013, date last accessed).
21 Okoli C, Siccardi M, Thomas-William S et al. Once daily maraviroc
300 mg or 150 mg in combination with ritonavir-boosted darunavir
800/100 mg. J Antimicrob Chemother 2012; 67: 671–4.
32 Muirhead G. An investigation of the effects of tenofovir on the
pharmacokinetics of the novel CCR5 inhibitor UK-427,857. In: Abstracts
of the Seventh International Congress on Drug Therapy in HIV Infection,
Glasgow, 2004. Abstract P282.
22 Kakuda TN, Abel S, Davis J et al. Pharmacokinetic interactions
of maraviroc with darunavir-ritonavir, etravirine, and etravirinedarunavir-ritonavir in healthy volunteers: results of two drug interaction
trials. Antimicrob Agents Chemother 2011; 55: 2290–6.
33 Croteau D, Best BM, Letendre S et al. Lower than expected maraviroc
concentrations in cerebrospinal fluid exceed the wild-type CC chemokine
receptor 5-tropic HIV-1 50% inhibitory concentration. AIDS 2012; 26:
890–3.
23 Comparative Trial of Maraviroc versus Emtricitabine/Tenofovir both
with Darunavir/Ritonavir in Antiretroviral-naive Patients Infected with
CCR5 Tropic HIV 1 (MODERN). http://clinicaltrials.gov/ct2/show/study/
NCT01345630 (14 January 2013, date last accessed).
34 Riddler SA, Haubrich R, DiRienzo AG et al. Class-sparing regimens
for initial treatment of HIV-1 infection. N Engl J Med 2008; 358:
2095– 106.
24 Garvey L, Latch N, Erlwein OW et al. The effects of a
nucleoside-sparing antiretroviral regimen on the pharmacokinetics of
ritonavir-boosted darunavir in HIV type-1-infected patients. Antivir Ther
2010; 15: 213–8.
25 Chittick GE, Zong J, Blum MR et al. Pharmacokinetics of tenofovir
disoproxil fumarate and ritonavir-boosted saquinavir mesylate
administered alone or in combination at steady state. Antimicrob
Agents Chemother 2006; 50: 1304 –10.
26 Taburet AM, Piketty C, Chazallon C et al. Interactions between
atazanavir-ritonavir and tenofovir in heavily pretreated human
35 Duvivier C, Ghosn J, Assoumou L et al. Initial therapy with nucleoside
reverse transcriptase inhibitor-containing regimens is more effective than
with regimens that spare them with no difference in short-term fat
distribution: Hippocampe-ANRS 121 Trial. J Antimicrob Chemother 2008;
62: 797–808.
36 Taiwo B, Zheng L, Gallien S et al. Efficacy of a nucleoside-sparing
regimen of darunavir/ritonavir plus raltegravir in treatment-naive
HIV-1-infected patients (ACTG A5262). AIDS 2011; 25: 2113– 22.
37 Gervasoni C, Cattaneo D. Pharmacokinetic concerns related to the
AIDS Clinical Trial Group (ACTG) A5262 trial. AIDS 2012; 26: 398–400;
author reply 397–8.
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