Raltegravir

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Raltegravir, better known as Isentress, (3l2v)

Better Known as: Isentress

  • Marketed By: Merck & Co.
  • Major Indication: Human Immunodeficiency Virus Infection
  • Drug Class: Retroviral Integrase Inhibitor
  • FDA Approval (Patent Expiration): 2007 (2022)
  • 2009 Sales: ~$1.1 Billion
  • Importance: It was the first drug of the Integrase Inhibitor class to be approved by the FDA. It offers a powerful new tool to be utilized in combination therapies against HIV infections.[1]
  • See Pharmaceutical Drugs for more information about other drugs and disorders.

Mechanism of Action

Retroviral Integrase is produced by the HIV retrovirus, enabling HIV to integrate its genetic material into the DNA of the infected cell. This integration step effectively transforms the infected cell into a permanent carrier of the viral genome, allowing the virus to persist and proliferate extensively.[2] HIV retroviral integrase forms "intasomes" when it . The integrase domains interact extensively with the viral DNA, precisely within an active site, in close proximity to the predicted target DNA into which the viral DNA will be inserted. Raltegravir binds with great specificity to the HIV integrase active site. It orients itself in such a way as to displace the reactive viral DNA end from the active site almost completely. to residues Asp 128, Asp 185, & Glu 221 via hydrogen bonds, has extensive π-stacking interactions with residues Tyr 212, Pro 214 and the final two nucleotide rings on one viral DNA strand. This disruption prevents the viral DNA from interacting with the target DNA, preventing integration and HIV proliferation.[3][4]

Pharmacokinetics

Retroviral Integrase Inhibitor Pharmacokinetics
Parameter Raltegravir Elvitegravir MK-2048
Tmax (hr) 1.8 2-4 N/A
Cmax (ng/ml) 4253 2070 N/A
Bioavailability (%) 32 ~30 N/A
Protein Binding (%) 83 N/A N/A
T1/2 (hr) 10.8 7.6 N/A
AUC (ng/ml/hr) 10168 21200 N/A
Dosage (mg) 400 150 N/A
Metabolism Hepatic - (UGT1A1) Hepatic - (CYP3A4) N/A

For Pharmacokinetic Data References, See: References

References

  1. Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, Loutfy MR, Lennox JL, Gatell JM, Rockstroh JK, Katlama C, Yeni P, Lazzarin A, Clotet B, Zhao J, Chen J, Ryan DM, Rhodes RR, Killar JA, Gilde LR, Strohmaier KM, Meibohm AR, Miller MD, Hazuda DJ, Nessly ML, DiNubile MJ, Isaacs RD, Nguyen BY, Teppler H. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008 Jul 24;359(4):339-54. PMID:18650512 doi:10.1056/NEJMoa0708975
  2. Savarino A. A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs. 2006 Dec;15(12):1507-22. PMID:17107277 doi:10.1517/13543784.15.12.1507
  3. Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. 2010 Mar 11;464(7286):232-6. Epub 2010 Jan 31. PMID:20118915 doi:10.1038/nature08784
  4. Hare S, Vos AM, Clayton RF, Thuring JW, Cummings MD, Cherepanov P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A. 2010 Oct 28. PMID:21030679 doi:10.1073/pnas.1010246107


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