In this article, we will discuss about Raltegravir (Overview). So, let’s get started.
Mechanism of Action
Raltegravir inhibits the catalytic activity of HIV-1 integrase, an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the covalent insertion, or integration of unintegrated linear HIV-1 DNA into the host cell genome preventing the formation of the HIV-1 provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection. Raltegravir did not significantly inhibit human phosphoryltransferases including DNA polymerases alpha, Beta and gamma.
Antiviral Activity in Cell Culture
Raltegravir at concentrations of 31±20 nM resulted in 95% inhibition (EC) of viral spread (relative to an untreated virus infected culture) in human T-lymphoid cell cultures infected with the cell line adapted HIV-1 variant H9III18. In addition, 5 clinical isolates of HIV-1 subtype B had Ecos values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells. In a single-cycle infection assay, raltegravir inhibited infection of 23 HIV-1 isolates representing 5 non-B subtypes (A,C,D,F, and G) and 5 circulating recombinant forms (AE, AG, BF, BG, and cpx) with EC50 values ranging from 5 to 12 nM. Raltegravir also inhibited replication of an HIV-2 isolate when tested in CEMx174 cells (EC) value = 6 nM). Additive to synergistic antiretroviral activity was observed when human T-lymphoid cells infected with the H9IIIB variant of HIV-1 were incubated with raltegravir in combination with non-
nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, or nevirapine); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, tenofovir, zalcitabine, or zidovudine); protease inhibitors (amprenavir. atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or
saquinavir); or the entry inhibitor enfuvirtide.
For the treatment of adult patients with HIV-1 infection, the dosage of Raltegravir (ISENTRESS®) is one 400 mg film-coated tablet administered orally, twice daily.
For the treatment of children and adolescents with HIV-1 infection, the dosage of Raltegravir (ISENTRESS®) is as follows:
• 12 years of age and older: One 400 mg film-coated tablet orally, twice daily
• 6 to less than 12 years of age: If at least 25 kg in weight:
(a) One 400 mg film-coated tablet orally, twice daily OR
(b) Chewable tablets: weight based to maximum dose 300 mg, twice daily
• If less than 25 kg in weight:
(a) Chewable tablets: weight based to maximum dose 300 mg, twice daily
• 2 to less than 6 years of age:
If at least 10 kg in weight:
(a) Chewable tablets: weight based to maximum dose 300 mg, twice daily.
Body weight (kg) – Dose – Number of Chewable Tablets
• 10kg to less than 14kg – 75 mg twice daily – 3 x 25 mg twice daily
• 14kg to less than 20kg – 100 mg twice daily – 1 x 100 mg twice daily
• 20kg to less than 28kg – 150 mg twice daily – 1.5 x 100 mg twice daily
• 28kg to less than 40kg – 200 mg twice daily – 2 x 100 mg twice daily
• at least 40kg – 300 mg twice daily – 3x 100 mg twice daily
The safety and tolerability profile of RAL is favorable. The most common adverse events noted in adults receiving RAL were abdominal distension, diarrhea, nausea, vomiting, fatigue, pyrexia, and headache. Overall, the safety profile in pediatric patients, including neonates, is similar to that observed in adults. RAL is metabolized primarily by UGT1A1 (the same metabolic pathway as bilirubin) and UGT1A1 activity is greatly reduced in neonates. Concerns regarding potential competition with bilirubin for albumin binding sites and resulting jaundice in infants have not been borne out. The dose recommended in neonates takes into
consideration the rapidly increasing UGT1A1 activity and drug clearance in this age group.
Severe, potentially life-threatening, and fatal skin reactions have been reported rarely. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic
failure. RAL should be discontinued if these events occur.
Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with RAL Myopathy and rhabdomyolysis have been reported. RAL should be used 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 thabdomyolysis, myopathy or increased serum creatine kinase.