Merck Presents New Pharmacokinetic Data on ISENTRESS® (raltegravir) at 14th European AIDS Conference
October 16, 2013 7:30 am ET
Company Confirms Development Program for Investigational Once Daily (QD) Dosing Regimen of ISENTRESS
Merck (NYSE:MRK), known as MSD outside the United States and Canada, is
presenting pharmacokinetic data this week on investigational
formulations of a once daily (QD) dose of ISENTRESS at the 14th
European AIDS Conference (EACS), sponsored by the European AIDS Clinical
Society. The meeting is currently taking place in Brussels, Belgium,
Oct. 16-19, 2013. The poster presentation A Single Dose Food Effect
Study of Raltegravir Formulations (Poster #PE10/17) will be
presented Thursday, Oct. 17, and Friday, Oct. 18, from 12:00 p.m. to
2:00 p.m. CET. Based on the results of this study and other data, Merck
plans to initiate a Phase III clinical study on a once daily dosing
regimen of ISENTRESS in early 2014, pending review by regulatory
agencies. ISENTRESS is administered twice daily, in accordance with the
approved Prescribing Information.
“We previously studied once daily ISENTRESS in a combination regimen and
in that study, the once daily formulation did not meet the
non-inferiority endpoint compared to twice daily ISENTRESS,” said Jeff
Chodakewitz, M.D., vice president, global clinical development,
infectious disease & vaccines, Merck Research Laboratories. “The data we
are presenting at the European AIDS Clinical Society conference, as well
as other currently available data, provide a strong scientific basis to
continue our investigational work toward a once daily dosing regimen.”
The primary endpoint of the previous Phase III trial (QDMRK) was
non-inferiority of the once daily 800 mg dose in a combination regimen
compared to the twice daily 400 mg dose in combination. The endpoint was
not met, as the once daily dose studied was inferior to the twice daily
dose. Results showed that at 48 weeks, 83 percent of treatment-naïve
adult HIV-1 infected patients achieved viral suppression with the dosing
regimen of 800 mg ISENTRESS (raltegravir) once daily, compared with 89
percent of patients treated with ISENTRESS 400 mg twice daily. Thus,
non-inferiority was not met in the QDMRK trial. The safety and
tolerability profiles of the two regimens were generally similar in the
study and similar to the Prescribing Information for ISENTRESS. The
study was concluded in 2010, and the results were presented at the 2011
Conference on Retroviruses and Opportunistic Infections (CROI) as well
as published in The Lancet.
The Single Dose Food Effect Study of Raltegravir Formulations
presented at EACS was an open-label, randomized, two cohort, three
period, three treatment, six sequence, crossover study in 36 healthy
subjects. The study evaluated the single dose pharmacokinetics and food
effect of two different formulations of raltegravir, both given in a
single 1200 mg dose at fasted, low-fat fed, and high-fat fed states. The
results indicated that both formulations have the potential to be
investigated further for once daily use in a clinical study, but showed
that the pharmacokinetics of the reformulated version of raltegravir
were less affected by food.
ISENTRESS is an integrase inhibitor indicated in combination with other
antiretroviral (ARV) agents for the treatment of HIV-1 infection in
adults. This indication is based on analyses of plasma HIV-1 RNA levels
in three double-blind controlled studies of ISENTRESS. Two of these
studies were conducted in clinically advanced, three-class ARV
[non-nucleoside reverse transcriptase inhibitor (NNRTI), nucleoside
reverse transcriptase inhibitor (NRTI), protease inhibitor (PI)]
treatment-experienced adult patients through 96 weeks and one was
conducted in treatment-naïve adults through 240 weeks. The use of other
active agents with ISENTRESS is associated with a greater likelihood of
Important Selected Safety Information
ISENTRESS does not cure HIV-1 infection or AIDS.
Severe, potentially life-threatening and fatal skin reactions have been
reported. This includes cases of Stevens-Johnson syndrome,
hypersensitivity reaction and toxic epidermal necrolysis. Immediately
discontinue treatment with ISENTRESS and other suspect agents if severe
hypersensitivity, severe rash, or rash with systemic symptoms or liver
aminotransferase elevations develop and monitor clinical status,
including liver aminotransferases closely.
Immune reconstitution syndrome can occur, including the occurrence of
autoimmune disorders with variable time to onset, which may necessitate
further evaluation and treatment.
Co-administration of ISENTRESS (raltegravir) with drugs that are strong
inducers of uridine diphosphate glucuronosyltransferase (UGT1A1) may
result in reduced plasma concentrations of raltegravir. Rifampin,
a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS.
Therefore, the dose of ISENTRESS for adults should be increased to 800
mg twice daily during coadministration with rifampin. There are no data
to guide co-administration of ISENTRESS with rifampin in patients below
18 years of age.
The most commonly reported (≥2%) drug-related clinical adverse reactions
of moderate to severe intensity in treatment-naïve adult patients
receiving ISENTRESS compared with efavirenz were insomnia (4% vs 4%),
headache (4% vs 5%), nausea (3% vs 4 %), fatigue (2% vs 3%), and
dizziness (2% vs 6%), respectively. Intensities were defined as follows:
Moderate (discomfort enough to cause interference with usual activity);
or Severe (incapacitating with inability to work or do usual activity).
Grade 2 to 4 creatine kinase laboratory abnormalities were observed in
patients treated with ISENTRESS (raltegravir). Myopathy and
rhabdomyolysis have been reported. Use with caution in patients at
increased risk of myopathy or rhabdomyolysis, such as patients receiving
concomitant medications known to cause these conditions and patients
with a history of rhabdomyolysis, myopathy or increased serum creatine
Rash occurred more commonly in treatment-experienced subjects receiving
regimens containing ISENTRESS plus darunavir/ritonavir, compared to
subjects receiving ISENTRESS without darunavir/ritonavir or
darunavir/ritonavir without ISENTRESS. However, rash that was considered
drug-related occurred at similar rates for all three groups. These
rashes were mild to moderate in severity and did not limit therapy;
there were no discontinuations due to rash.
ISENTRESS should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus. To monitor maternal-fetal
outcomes of pregnant patients exposed to ISENTRESS, an Antiretroviral
Pregnancy Registry has been established. Physicians are encouraged to
register patients by calling 1-800-258-4263.
About ISENTRESS (raltegravir)
ISENTRESS is Merck’s integrase inhibitor for the treatment of HIV-1
infection in adult patients and pediatric patients ages 2 years and
older and weighing at least 10 kg as part of combination HIV therapy.
ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA
by the integrase enzyme and has demonstrated rapid antiviral activity.
Inhibiting integrase from performing this essential function limits the
ability of the virus to replicate and infect new cells. ISENTRESS
(raltegravir) is now approved in combination therapy in more than 76
countries for use in treatment-naïve adult patients with HIV-1 and in
more than 110 countries for use in treatment-experienced adult patients
with HIV-1. ISENTRESS, in combination therapy, for use in pediatric
patients with HIV-1 has also been approved for use in 33 countries.
Merck is continuing to move forward with filings in additional countries
around the world.
To assist patients taking ISENTRESS, Merck offers the SUPPORT™ program,
which provides personal support and patient advocacy regarding
individual reimbursement issues. For more information about the SUPPORT™
program, please visit www.merckhelps.com
or call 1-800-850-3430.
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Please see Prescribing Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_pi.pdf
and Patient Information for ISENTRESS at http://www.merck.com/product/usa/pi_circulars/i/isentress/isentress_ppi.pdf.
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