Antiretroviral Activity, Pharmacokinetics, and Tolerability of
MK-0518, a Novel Inhibitor of HIV-1 Integrase, Dosed As Monotherapy
for 10 Days in Treatment-Naive HIV-1-Infected Individuals
JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 43(5) 15
December 2006 pp 509-515
[Rapid Communication]
Markowitz, Martin MD*; Morales-Ramirez, Javier O MD†; Nguyen,
Bach-YYen MD‡; Kovacs, Colin M MD§; Steigbigel, Roy T MD‖; Cooper,
David A MD, DSc¶; Liporace, Ralph MD#; Schwartz, Robert MD**; Isaacs,
Robin MD‡; Gilde, Lucinda R BS‡; Wenning, Larissa PhD‡; Zhao,
Jinging PhD‡; Teppler, Hedy MD‡; and the Protocol 004 Study Team
Abstract
Background: MK-0518 is a novel HIV-1 integrase strand transfer
inhibitor with potent in vitro activity against HIV-1 (95% inhibitory
concentration [IC95] = 33 nM in 50% human serum) and good
bioavailability in uninfected subjects. This study explored the
antiretroviral activity and safety of MK-0518 versus placebo for 10
days as monotherapy in antiretroviral therapy-naive HIV-1-infected
patients with plasma HIV-1 RNA levels of at least 5000 copies/mL and
CD4+ T-cell counts of at least 100 cells/mm3.
Methods: This was a multicenter, double-blind, randomized,
placebo-controlled 2-part study, with the first part using MK-0518 in
1 of 4 doses (100, 200, 400, and 600 mg) versus placebo (randomized
1:1:1:1:1) given twice daily for 10 days of monotherapy. Patients were
monitored for safety, pharmacokinetic parameters, and antiretroviral
effect.
Results: Thirty-five patients were enrolled (6-8 patients per
treatment group) and completed 10 days of therapy; the mean baseline
log10 HIV RNA level ranged from 4.5 to 5.0 copies/mL in each group. On
day 10, the mean decrease from baseline in the log10 HIV RNA level was
-0.2 copies/mL for the placebo group and -1.9, -2.0, -1.7 and -2.2
log10 copies/mL for the MK-0518 100-, 200-, 400-, and 600-mg treatment
groups, respectively. All dose groups had superior antiretroviral
activity compared with placebo (P < 0.001 for comparison of each dose
with placebo). At least 50% of patients in each MK-0518 dose group
achieved an HIV RNA level <400 copies/mL by day 10. Mean trough
MK-0518 concentrations at each dose exceeded the IC95 of 33 nM. Study
therapy was generally well tolerated. The most common adverse
experiences were headache and dizziness; these were similar between
active and control groups. There were no discontinuations because of
adverse experiences and no serious adverse experiences.
Advances in the understanding and treatment of HIV-1 infection have
dramatically altered the morbidity and mortality associated with HIV-1
infection.1,2 Current therapies have been shown to exert potent and
durable antiviral effects associated with immune reconstitution. Yet,
the HIV-1 treatment landscape remains far from ideal.
The need for new drugs is constant and is a reflection of myriad
issues. First and foremost are short- and long-term drug toxicities.
In addition, primary and secondary drug resistance remains a serious
problem. Currently, up to 25% of those newly infected harbor a virus
resistant to at least 1 antiviral agent.3 Recent data suggest that
primary resistance to nonnucleoside reverse transcriptase inhibitors
in a variety of populations, including women using single-dose
nevirapine to prevent mother-to-child transmission,4 adolescents,5 and
men who have sex with men,3 may be as high as 15%.
Currently available oral medications in common use essentially target
the viral reverse transcriptase or protease enzymes. The third enzyme
encoded by the viral polymerase is integrase. HIV-1 integrase is
encoded solely by the HIV-1genome and is essential for viral
replication. Integrase inserts the viral DNA into the cellular genome
via a pathway that includes 2 distinctive catalytic reactions: the 3_
endonucleolytic processing of the viral DNA ends and the subsequent
strand transfer or integration of viral and cellular DNA.6,7 Loss of
integrase activity results in the inability of the virus to complete
its life cycle, and therefore provides a unique and specific antiviral
target for drug development. The work of Hazuda and colleagues8 paved
the way for the identification of clinically relevant inhibitors of
HIV-1 integrase. With the development of a reliable biochemical
screen, selective compounds that act as strand transfer inhibitors
with antiviral activity have been identified and tested.8 One of these
integrase inhibitors, L-000870812, exhibited highly robust antiviral
activity in rhesus macaques infected with an HIV-simian
immunodeficiency virus (SIV) chimeric virus, with a reduction in
levels of plasma RNA from 107 to <250 copies/mL.9
MK-0518 is an investigational HIV-1 integrase inhibitor with potent in
vitro activity, exhibiting a 95% inhibitory concentration (IC95) of 33
nM in the presence of 50% human serum. It is active against a wide
range of wild-type and multidrug-resistant HIV-1 clinical isolates and
has potent activity against viruses using CCR5 and/or CXCR4
coreceptors for entry.10,11 We present here the initial results of a
10-day monotherapy proof-of-concept study to establish the antiviral
activity, pharmacokinetic (PK) profile, and tolerability of MK-0518 in
a cohort of antiretroviral therapy (ART)-naive HIV-1-infected
individuals.12 This article reports the data from the first part of a
2-part study in which the monotherapy phase is followed by a longer
term combination therapy phase trial of MK-0518 versus efavirenz, each
combined with 2 nucleoside reverse transcriptase inhibitors.
METHODS
This was a multicenter, double-blind, randomized, placebo-controlled,
dose-ranging study conducted in the United States, Australia, and
Canada, which enrolled 35 HIV-infected patients who were ART naive.
The protocol was approved by the institutional review board or ethical
review committee of each of the 11 participating sites; written
informed consent was obtained from each subject before study entry.
Study Population
Male and female subjects aged 18 years or older were eligible for the
study if they were HIV-1-seropositive and had a plasma HIV-1 RNA level
of 5000 copies/mL or greater and a CD4+ T-cell count of at least 100
cells/mm3 at screening. Patients were excluded if they received any
form of approved or experimental ART or were previously treated with
adefovir or lamivudine for any other viral infection for more than 7
days. Eligibility criteria also included hemoglobin ≥9.0 g/dL
(female subject) or ≥10.0 g/dL (male subject); absolute neutrophil
count ≥1000 cells/mm3; platelet count >100,000 cells/mm3; bilirubin
≤ upper limit of normal (ULN); alkaline phosphatase, aspartate
aminotransferase (AST), and alanine aminotransferase (ALT) all <1.5
times ULN; and creatinine within normal limits. Patients were excluded
for evidence of active hepatitis, including hepatitis B and C virus,
and for use of immune-based therapy or investigational agents within 1
month of study treatment. Prohibited medications included
carbamazepine, phenobarbital, phenytoin, primidone, rifabutin,
rifampin, herbal remedies such as St. John's wort and garlic
supplements, and gemfibrozil. In addition, anticipating the use of
efavirenz in part 2 of this study, medications contraindicated for use
with efavirenz were prohibited in this study.
Study Design
This was the first part of a multicenter, double-blind (with in-house
blinding), randomized, controlled, 2-part, dose-ranging study in
ART-naive patients with HIV infection. Patients were stratified at
entry by initial plasma HIV-1 RNA level (> or <50,000 copies/mL) and
randomly assigned to 1 of 5 treatment groups for 10 days: MK-0518 (4
dose levels) or a matching placebo administered orally, without regard
to food, at a dose strength of 100, 200, 400, or 600 mg twice daily.
Central randomization with an interactive voice response system was
used. Medication adherence was assessed by diary card and pill count.
Study patients were seen in the clinic at screening; randomization
(day 1); on days 2, 3, 4, 5, 8, and 10; and 14 days after treatment
termination (day 24). Physical examination and safety laboratory
assessments were performed at screening and on days 1, 5, 10, and 24.
Pregnancy tests were performed on female patients of childbearing
potential at screening and randomization (day 1). Plasma was collected
for HIV-1 RNA levels at screening; before the first dose; 6 and 12
hours after the dose on day 1; and on days 2, 3, 4, 5, 8, 10, and 24.
Plasma HIV-1 RNA levels were determined using the AMPLICOR HIV-1
Monitor Assay, version 1.5; if the result was below the level of
quantification (LoQ) of 400 copies/mL, the UltraSensitive HIV-1
Monitor Assay (LoQ = 50 copies/mL) was used (both by Roche Molecular
Diagnostics, Alameda, CA). A full PK profile was performed after the
morning dose on day 10; plasma was collected before the first dose and
0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after the dose and was
shipped to BASi Northwest Laboratory (McMinnville, OR). Patients
fasted overnight before the day 10 PK sampling and remained fasted
until 〜4 hours after dosing; after that time, there were no dietary
restrictions. Drug concentrations were determined via high-performance
liquid chromatography mass spectrometry/mass spectrometry (HPLC-MS/MS)
using a validated assay with a lower LoQ of 2 ng/mL (4.5 nM) (Clinical
Drug Metabolism; Merck Research Laboratories, West Point, PA,
unpublished data). All patients who received study medication were
included in the analysis of tolerability. Patients were evaluated for
the occurrence of adverse events at each study visit. Laboratory
monitoring included a complete blood cell count with differential and
platelets and a full chemistry panel, including liver function tests,
blood urea nitrogen (BUN), creatinine, amylase, lipase, electrolytes,
and a fasting lipid profile. All safety laboratory results obtained
and adverse events that occurred while subjects were on study therapy
or within 14 days after discontinuation of study therapy were
included.
Statistical Analyses
Antiretroviral Activity
The study hypothesis tested whether MK-0518 given twice daily for 10
days at the specified doses has superior antiviral activity compared
with placebo, as measured by differences from baseline to day 10 in
plasma HIV-1 RNA level (log10 copies/mL). If the difference of change
from baseline in HIV RNA on day 10 between the MK-0518 groups and the
placebo group is at least 1.5 log10, with a sample size of more than 6
patients per treatment group, it would give a power of >99.3% to claim
that MK-0518 is superior to placebo. Plasma HIV-1 RNA changes were
calculated based on levels measured by the AMPLICOR HIV-1 Monitor
Standard Assay (version 1.5) with an LoQ of 400 copies/mL. Baseline
measurements were defined as the randomization/day 1 value before
dosing for each patient. HIV-1 RNA values less than the LoQ were
imputed as LoQ (400 copies/mL) if a signal was detected or as 0.5
times the LoQ (200 copies/mL) if no signal was detected. Two-sided 95%
confidence intervals (CIs) for the difference in changes from baseline
in plasma HIV-1 RNA (log10 copies/mL) at each time point between each
dose of MK-0518 and placebo were estimated using the t-distribution.
The proportion of patients achieving HIV-1 RNA levels less than the
LoQ of the AMPLICOR HIV-1 Monitor Standard Assay (400 copies/mL), the
proportion of patients achieving HIV-1 RNA levels less than the LoQ of
the UltraSensitive HIV-1 Monitor Assay (50 copies/mL), and change from
baseline in CD4 cell counts were also summarized.
Steady-State Pharmacokinetics
Plasma concentrations in molar units (nM) and nominal sampling times
were used to determine PK parameters for each subject. The area under
the plasma concentration curve over the dosing interval (AUC0-12h) was
calculated using the linear trapezoidal method for ascending
concentrations and the log trapezoidal method for descending
concentrations. Maximum plasma concentrations (Cmax), time to Cmax
(Tmax), and the plasma concentration at the end of the dosing interval
(C12h, trough) were obtained by inspection of the plasma concentration
data. For the PK data, summary statistics for the PK parameters C12h,
AUC0-12h, Cmax, and Tmax are presented by dose group.
Adverse Events
All clinical and laboratory adverse experiences were summarized by
treatment group. The maximum intensity of clinical adverse experiences
was reported according to the following criteria: mild (awareness of
sign or symptom but easily tolerated), moderate (discomfort enough to
cause interference with usual activity), and severe (incapacitating
with inability to work or do usual activity). Safety laboratory values
during treatment and follow-up were examined according to the 1992
Division of AIDS (DAIDS) toxicity guidelines for adults (available at:
http://rcc.tech-res-intl.com/tox_tables.htm ) as well. Formal
statistical testing was neither prespecified nor performed. Because
this study is currently ongoing in the blind combination therapy
phase, these data are presented as combined across the MK-0518 groups
to avoid unblinding of the treatment assignments.
RESULTS
Study Subjects
Of the 35 patients enrolled, 94% were male, 63% were white, and the
mean age was 40 years (Table 1). Twenty-eight patients received
MK-0518 (7 on 100 mg twice daily, 7 on 200 mg twice daily, 6 on 400 mg
twice daily, and 8 on 600 mg twice daily) and 7 received a placebo
twice daily. All patients completed the 10-day monotherapy treatment
period. The mean baseline log10 HIV RNA levels were 4.65, 4.53, 4.58,
and 4.97 log10 copies/mL for the 4 MK-0518 dose groups, respectively,
and 4.77 log10 copies/mL for the placebo group (see Table 1).
Antiretroviral Activity and Pharmacokinetics
All treated subjects responded to MK-0518 (Fig. 1). The viral decay
rates were similar among all MK groups, and each was significantly
greater compared with placebo (P < 0.001). There were no differences
in the slope of HIV RNA decline (log10 copies/mL/d) from day 1 to day
10 for patients by stratification variable of entry HIV RNA level > or
<50,000 copies/mL. Nevertheless, a greater decline from baseline at
day 10 was observed in those with higher baseline RNA values, whereas
patients with lower baseline RNA values more frequently achieved RNA
levels <400 copies/mL by day 10. By day 10, mean decreases in log10
HIV RNA level of 1.93, 1.98, 1.66 and 2.16 copies/mL were observed for
MK-0518 administered at doses of 100, 200, 400, and 600 mg twice
daily, respectively, and all were significantly greater than that
observed for the placebo group (P < 0.001 for all groups) (Fig. 2;
Table 2). There was no apparent dose response, and no statistically
significant differences were observed among the MK-0518 dose groups.
By day 10, the proportions of patients achieving HIV RNA levels <400
copies/mL were 57% (4 of 7 patients), 57% (4 of 7 patients), 50% (3 of
6 patients), and 50% (4 of 8 patients) for groups administered MK-0518
at doses of 100, 200, 400, and 600 mg twice daily, respectively. None
of the placebo recipients achieved HIV RNA levels <400 copies/mL.
Plasma HIV RNA levels <50 copies/mL by UltraSensitive assay were also
observed by day 10 for at least 1 patient in each MK-0518 group (see
Table 2). Numeric increases in CD4 cell count were observed on day 10
for all MK-0518 dose groups, but these changes were not statistically
significant (data not shown).
TABLE 2. Antiretroviral Activity of MK-0518
On day 10, a PK evaluation was performed on all subjects as detailed
previously. Geometric mean plasma concentrations of MK-0518 at trough
(C12h) were lowest in the 100-mg dose group and increased with dose.
Geometric mean values for Cmax and AUC0-12h increased up to the 400-mg
dose and were similar for the 400 and 600 mg regimens (Table 3).
Because of the close spacing between these doses and fairly large
intersubject variability in the PK profiles, it is not clear if this
represents a true lack of dose proportionality or is just a reflection
of the variability and small number of patients in each dose group.
Half-life values could not be accurately estimated in this study, but
the data seem to be generally consistent with the plasma concentration
profile shape previously observed in healthy volunteers, where MK-0518
concentrations declined from Cmax in a biexponential manner with an
initial half-life of approximately 1 hour and a terminal half-life of
approximately 7 to 12 hours (Fig. 3).13 The C12h plasma concentrations
(geometric mean) in all dosing groups exceeded 33 nM, the mean in
vitro IC95 of MK-0518 for wild-type HIV-1 in the presence of 50%
normal human serum. Although 3 of 6 individuals in the 100-mg dosing
group had MK-0518 C12h levels less than the IC95 of 33 nM, these 3
patients achieved HIV RNA values <400 copies/mL or a >2 log10 decline
in HIV RNA by day 10.
TABLE 3.PK Parameters of MK-0518 at Day 10
Tolerability of MK-0518
Overall, MK-0518 was generally well tolerated. There were no serious
adverse experiences and no discontinuations because of adverse
experiences. Clinical adverse experiences, irrespective of drug
relation, were reported in 19 of 35 patients; these were generally
transient and mild to moderate in severity. Headache and dizziness
were most commonly reported across the treatment groups, including the
placebo group. Drug-related clinical adverse experiences were reported
in 8 patients among the 4 MK-0518 treatment groups and in 2 patients
in the placebo group and included constipation, flatulence, stomach
discomfort, chills, fatigue, malaise, anorexia, dizziness, headache,
disorientation, increased heart rate, and hyperhidrosis; all were mild
or moderate in intensity (Table 4). There were no apparent
dose-related toxicities.
One laboratory adverse experience in the MK-0518 100-mg group of
increased ALT was reported on day 5 (grade 1 per DAIDS criteria) and
was considered to be drug related. This adverse experience resolved by
day 10 without interruption of therapy. No other laboratory adverse
experiences were reported. No grade 3 or 4 laboratory toxicities were
observed.
DISCUSSION
This first study of MK-0518 in HIV-1-infected individuals
unequivocally demonstrates its robust antiretroviral activity,
favorable PK profile, and short-term tolerability when given twice
daily at 100, 200, 400, and 600 mg dosing levels. PK parameters were
in a similar range as those reported for HIV-1-uninfected subjects.13
Geometric mean values for C12h exceeded the IC95 in 50% human serum at
all doses, which is consistent with twice-daily dosing. The
approximately 2-fold log reduction in HIV-1 plasma viral load over 10
days is comparable to that observed with potent antiretroviral agents
that target HIV-1 reverse transcriptase or protease and to the
antiretroviral effect seen when combinations of at least 3
antiretroviral agents are used.14-16 The antiretroviral activity was
comparably robust at all doses tested, with at least half of patients
reaching plasma HIV-1 RNA levels <400 copies/mL by day 10 of
monotherapy. There was no evidence to show a PK/pharmacodynamic
relation, because all MK-0518 groups responded well (ie, the entire
range of PK parameter values observed in this study was associated
with pharmacodynamic efficacy). Based on these results, the second
phase of this study has been initiated, during which MK-0518 at the 4
doses studied is to be compared with efavirenz dosed once daily, all
coadministered with once-daily tenofovir and lamivudine.
Certain properties of MK-0518 are important considerations for its
clinical use. It is primarily metabolized by the liver via
glucuronidation and is neither an inducer nor an inhibitor of
CYP3A4.17,18 This should clearly reduce potential drug interactions
with other commonly used antiretroviral agents, especially the
currently available protease inhibitors and nonnucleoside reverse
transcriptase inhibitors. Specifically, there is no potential or need
for boosting with CYP3A4 inhibitors such as ritonavir. Thus, use in
salvage regimens, where the need is most acute, should be less
complicated. Of note, there are no immediate changes in triglyceride
or cholesterol levels (data not shown) such as may be seen with
ritonavir and other protease inhibitors. Larger scale testing in
various HIV-1-infected populations is currently underway and,
ultimately, should better define the complete side effect profile of
MK-0518. The introduction of a clinically relevant inhibitor of HIV-1
integrase represents a major advance in basic and clinical science.
Efforts to target all 3 constitutive virally encoded enzymes required
for viral replication have been accomplished successfully. How these
compounds may ultimately be incorporated into the antiretroviral
arsenal remains to be defined. Interim results from phase 2 trials in
treatment-naive and treatment-experienced HIV-1-infected subjects
harboring multidrug-resistant HIV-1 in combination regimens and at
doses similar to those used in this study demonstrated that after 16
to 24 weeks, MK-0518 has sustained antiretroviral activity without
substantial toxicity.19,20 If this observation is confirmed in the
phase 3 studies now underway, MK-0518 should clearly be a welcome
addition to the existing treatment options for those persons infected
with HIV-1.
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