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).

OPEN CLINICAL TRIALS

Click here for information on clinical trials of raltegravir.

FURTHER READING

Isentress Prescribing Information

Isentress Patient Product 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.

A Study to Evaluate the Safety and Efficacy of MK-0518 in HIV-Infected Patients Failing Current Antiretroviral Therapies.

A Study to Evaluate the Safety and Efficacy of MK-0518 in HIV-Infected Patients Failing Current Antiretroviral Therapies.

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.