|
 INTRODUCTION
•
The
U.S. Food and Drug Administration (FDA) approved
raltegravir (Isentress) on October 12, 2007,
for use as part of combination antiretroviral
therapy in treatment-experienced adult HIV patients.
•
Raltegravir
(previously known as MK-0518) belongs to the
class of drugs known as integrase inhibitors.
These drugs suppress HIV replication by inhibiting
the activity of the integrase enzyme of HIV,
which prevents the virus from inserting its
DNA into the host cell. Raltegravir is the first
integrase inhibitor to be approved by the FDA.
•
Approval
of raltegravir was based in part on results
from the ongoing Phase III BENCHMRK trials,
which found that after 24 weeks, 400 mg twice-daily
raltegravir in combination with optimized background
therapy (OBT) led to significant reductions
in HIV viral load and increases in CD4 counts
(see Efficacy, below).
DOSING
•
Raltegravir
is an oral drug, and the recommended dose for
treatment-experienced patients is one 400 mg
tablet twice daily, in combination with other
antiretroviral drugs. No dosage adjustment is
necessary in patients with mild to moderate
hepatic or severe renal impairment (Isentress
Prescribing Information, October
2007).
PHARMACOLOGY
•
Administration
of raltegravir following a high-fat meal increased
the raltegravir area under the concentration-time
curve (AUC) by approximately 19%. A high-fat
meal slowed the rate of absorption, resulting
in an approximately 34% decrease in the maximum
plasma concentration (Cmax), an 8.5-fold increase
in the plasma concentration at 12 hours, and
a delay in the time to maximum concentration
(Tmax) following a single 400 mg dose.
•
The
effect of consumption of a range of food types
on steady-state raltegravir pharmacokinetics
(PK) is not known. Raltegravir was administered
without regard to food in pivotal safety and
efficacy studies of HIV-infected patients.
•
With
twice-daily dosing, PK steady state is achieved
within approximately the first 2 days of dosing.
Considerable variability was observed in the
PK of raltegravir in clinical trials. Among
study participants receiving 400 mg twice-daily
raltegravir, drug exposures were characterized
by a geometric mean AUC within the first 12
hours of 14.3 mcM(hr) and a plasma concentration
at 12 hours of 142 nM. The absolute bioavailablilty
of raltegravir has not been established.
EFFICACY
Treatment-experienced patients
A
Phase II, randomized, double-blind, placebo-controlled
trial included 179 treatment-experienced patients
who had a viral load greater than 5000 copies/mL,
were failing HAART, and had resistance to at
least 1 drug in each of the 3 major antiretroviral
drug classes. Participants received 200, 400,
or 600 mg twice-daily doses of raltegravir or
else placebo, all with OBT.
At Week 24, HIV RNA decreased by a mean 1.80-1.87
log10 copies/mL in the raltegravir arms, compared
with 0.35 log10 copies/mL in the placebo group;
65% of patients taking raltegravir achieved
an undetectable HIV viral load below 50 copies/mL.
Three patients (2%) across all raltegravir-treated
arms and 1 (2%) in the placebo group discontinued
the study because of adverse events; 14 (11%)
across all raltegravir-treated arms and 27 (60%)
in the placebo group discontinued due to lack
of efficacy (Lancet 369(9569): 1261-1269.
April 14, 2007).
The 400 mg twice-daily raltegravir dose was
selected as having the best efficacy/safety
profile. After 48 weeks, 64% of patients who
continued on this dose had a viral load below
50 copies/mL, while CD4 count increased by 110
cells/mm3 (47th ICAAC, 2007, abstract H-713).
 The
twin BENCHMRK trials included about 700 treatment-experienced
patients with documented antiretroviral drug
resistance in North and South America, Europe,
and Asia. Participants were randomly assigned
to receive 400 mg twice-daily raltegravir or
placebo, all with OBT. After 24 weeks, participants
who took raltegravir were about twice as likely
to achieve a viral load below 50 copies/mL than
those taking placebo (63% vs 34%, respectively).
CD4 cell gains were also larger in the raltegravir
arm (85 vs 35 cells/mm3, respectively). Raltegravir
worked best in people who started another active
drug at the same time (14th CROI, 2007, abstracts
150aLB and 150bLB).
Treatment-naive
patients
The
anti-HIV activity of raltegravir has also been
studied in patients starting treatment for the
first time. A dose-ranging trial compared 10-day
raltegravir monotherapy in 28 treatment-naive
patients versus placebo in 7 patients. At least
50% of patients in each raltegravir dose group
achieved a viral load below 400 copies/mL by
Day 10. (JAIDS 43(5): 509-15, December
15, 2006).
After
16 weeks of therapy, patients receiving raltegravir
doses of 100, 200, 400, or 600 mg twice daily
achieved greater than 50-fold viral load reductions.
Viral load decreased to less than 400 copies/mL
in 50%-57% of patients, and to less than 50
copies/mL in 13%-29%. All raltegravir dose groups
had statistically superior antiretroviral activity
compared with placebo.
In
the second part of the study, 198 treatment-naive
patients were randomly assigned to receive either
the same doses of twice-daily raltegravir or
600 mg once-daily efavirenz (Sustiva), both
in combination with 3TC/tenofovir (Truvada).
Viral load became undetectable more rapidly
in patients who received raltegravir at any
dose than in those who received efavirenz. By
week 24, however, outcomes in all treatment
arms were similar. Across all arms, 85%-95%
of patients achieved a viral load below 50 copies/mL.
After 48 weeks, 83%-88% maintained virological
suppression at this level.
Virological
failure before week 48 was observed in 3% of
patients taking raltegravir and 3% taking efavirenz.
Of the 5 patients who experienced failure on
raltegravir, 2 had virus with the N155H amino
acid substitution, a mutation known from in
vitro experiments to be selected by raltegravir.
(4th IAS, 2007, abstract TuAb104 & JAIDS
46(2):125-33, October 1, 2007).
ADVERSE
EVENTS / TOXICITY
Studies
have shown that raltegravir is generally safe
and well tolerated. In Phase II studies in treatment-experienced
patients, the most commonly reported treatment-related
adverse effects were diarrhea, nausea, fatigue,
headache, and itching. Other reported adverse
effects included constipation, flatulence, and
sweating. Overall, the adverse effects of raltegravir
were comparable to those in the placebo arm.
In
the BENCHMRK trials, less than 2% of study participants
discontinued therapy due to adverse events.
The most common adverse events of all intensities,
regardless of causality, were nausea, diarrhea,
headache, and fever. Additionally, Grade 2 to
4 creatine kinase laboratory abnormalities were
observed in the raltegravir arm (Isentress
Prescribing Information, p. 4).
In
the Phase II study of treatment-naive patients,
the most common adverse events occurring after
24 weeks of treatment were headache, dizziness,
and nausea. Eight serious, non drug-related
adverse effects occurred overall (7/160 in the
raltegravir arm and 1/38 in the efavirenz arm);
1 patient taking 600 mg twice-daily raltegravir
discontinued treatment due to elevated liver
function tests.
Although
some early data indicated that more people taking
raltegravir developed cancer, this was later
attributed to an unusually low rate of cancer
among patients taking placebo, and the rates
evened out with longer follow-up. Long-term
carcinogenicity studies of raltegravir in rodents
are ongoing. No evidence of mutagenicity or
genotoxicity was observed in vitro during microbial
mutagenesis tests, assays for DNA breakage,
or in vitro and in vivo during chromosomal aberration
studies.
Manufacturer
Merck notes that because clinical trials are
conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials
of a drug cannot be compared directly to rates
in the clinical trials of other drugs, and may
not reflect rates observed in practice (Isentress
Prescribing Information, p. 2).
Immune
reconstitution syndrome has been reported in
patients treated with combination antiretroviral
therapy, which may include raltegravir-containing
regimens. During the initial phase of HAART,
a patient whose immune system improves may develop
an inflammatory response to indolent or residual
opportunistic infections (e.g., Mycobacterium
avium, cytomegalovirus, Pneumocystis
pneumonia, tuberculosis, varicella zoster virus),
which may necessitate further evaluation and
treatment (Isentress
Prescribing Information, p. 2).
FERTILITY
AND PREGNANCY
No
effect on fertility was seen in male or female
rats at raltegravir doses up to 600 mg/kg/day,
which resulted in an exposure 3-fold greater
than the exposure seen with the recommended
human dose (Isentress
Prescribing Information, p. 10).
Raltegravir
is in FDA Pregnancy Category C. No adequate
or well-controlled studies of raltegravir have
been done in pregnant women. Also, no PK studies
have been conducted to date in pregnant women.
In animal studies, no treatment-related effects
on embryonic/fetal survival or fetal weight
were observed in rabbits (up to 1000 mg/kg/day)
or rats (up to 600 mg/kg/day) receiving up to
3- to 4-fold the exposure at the recommended
human dose. No treatment-related external, visceral,
or skeletal changes were observed in rabbits.
Raltegravir
should be used during pregnancy only if clearly
needed. To monitor maternal and fetal outcomes
of pregnant women exposed to raltegravir and
other antiretroviral agents, physicians may
access an Antiretroviral Pregnancy Registry.
Physicians may register patients online at www.APRegistry.com
or by calling 1-800-258-4263.
It
is not known whether raltegravir or its metabolites
are distributed in human breast milk; however,
raltegravir is secreted into the milk of lactating
rats. Because of both the potential for HIV
transmission and serious adverse reactions in
nursing infants, HIV positive mothers should
not breast-feed their infants if they are taking
raltegravir (Isentress
Prescribing Information, p. 6).
DRUG
AND FOOD INTERACTIONS
Based
on the results of drug interaction studies and
clinical trials, no dose adjustment of raltegravir
is required when raltegravir is co-administered
with other antiretroviral agents (Merck press
release, October 12, 2007).
The
addition of enfuvirtide
(T-20; Fuzeon) to a raltegravir-containing
regimen appears to increase virological response.
A 24-week analysis of 1 dose-ranging study of
treatment-experienced participants found that
viral load decreased to less than 400 copies/mL
in 60% of participants receiving raltegravir
monotherapy and 90% of patients receiving raltegravir
plus enfuvirtide.
Raltegravir
should be used with caution when administered
with strong inducers of UGT1A1, including rifampin.
These may reduce plasma concentrations of raltegravir
(Isentress
Prescribing Information, p. 2).
As
with rifampin, ritonavir-boosted
tipranavir (Aptivus) reduces plasma concentrations
of raltegravir. However, in clinical trials,
comparable raltegravir efficacy was observed
in this treatment subgroup when compared with
study participants not receiving tipranavir
(Isentress
Prescribing Information, p. 6).
Drugs
that inhibit UGT1A1 may increase plasma levels
of raltegravir. Clinical trial data suggested
that concomitant use of raltegravir plus ritonavir-boosted
atazanavir (Reyataz),
a strong inhibitor of UGT1A1, increased plasma
concentrations of raltegravir. However, this
increase was not significant enough to warrant
dose adjustment when co-administering raltegravir
with atazanavir (Isentress
Prescribing Information, p. 6).
FURTHER
READING
Isentress
Prescribing Information
B
Grinsztejn, N Bach-Yen, C Katlama, and others.
Safety and efficacy of the HIV-1 integrase inhibitor
raltegravir (MK-0518) in treatment-experienced
patients with multidrug-resistant virus: a phase
II randomized controlled trial. The Lancet
369(9569): 1261-1269. April 14, 2007.
B
Grinsztejn, B Nguyen, C Katlama, and others.
48 week efficacy and safety of MK-0518, a novel
HIV-1 integrase inhibitor, in patients with
triple-class resistant virus. 47th Interscience
Conference on Antimicrobial Agents and Chemotherapy
(ICAAC). Chicago, September 17-20, 2007. Abstract
H-713.
M Markowitz, J O Morales-Ramirez, B-Y Nguyen,
and others. 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.
Journal of Acquired Immune Deficiency Syndromes
43(5): 509-515. December 15, 2006.
D Cooper, J Gatell, J Rockstroh, and others.
Results from BENCHMRK-1, a phase III study evaluating
the efficacy and safety of MK-0518, a novel
HIV-1 integrase inhibitor, in patients with
triple-class resistant virus. 14th Conference
on Retroviruses and Opportunistic Infections
(CROI). Los Angeles, February 25-28, 2007. Abstract
105aLB.
R Steigbigel, P Kumar, J Eron, and others. Results
from BENCHMRK-2, a phase III study evaluating
the efficacy and safety of MK-0518, a novel
HIV-1 integrase inhibitor, in patients with
triple-class resistant virus. 14th CROI. Abstract
105bLB.
M Markowitz, BY Nguyen, E Gotuzzo, and others.
Rapid and Durable Antiretroviral Effect of the
HIV-1 Integrase Inhibitor Raltegravir as Part
of Combination Therapy in Treatment-Naive Patients.
JAIDS 46(2):125-33. October 1, 2007.
Merck
& Co. FDA Approves ISENTRESS (raltegravir)
Tablets, First-in-Class Oral HIV-1 Integrase
Inhibitor. Press release. October 12,
2007.
Manufacturer
Information
Isentress
Merck & Company, Inc
One Merck Dr
P.O. Box 100
Whitehouse Station, NJ 08889-0100
(800) 609-4618
1/29/08
Sources
NIAID. Fact Sheet on Isentress.
|
