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Emerging role of integrase inhibitors in the management of treatment-experienced patients with HIV infection.

Katlama C, Murphy R - Ther Clin Risk Manag (2009)

Bottom Line: Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development.Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed.The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

View Article: PubMed Central - PubMed

Affiliation: Pierre et Marie Curie Université - Paris 6, Service de Maladies Infectieuses et Tropicales, Paris, France.

ABSTRACT
Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development. Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed. Two drugs in this class have reached late stages of development for use in HIV-1 infected individuals: raltegravir, which has just been approved for use in treatment-experienced patients, and elvitegravir, currently in phase III trials. Both are potent with an IC(50) in the 30 nM range and active in vitro against wild type as well as in strains highly resistant to all other existing classes of drugs. Clinical trials in both treatment-naïve and -experienced patients have demonstrated raltegravir to be highly effective with an excellent tolerability profile and no specific clinical or metabolic side effects. Longer follow up is necessary to ensure this early safety profile is sustained. The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

No MeSH data available.


Related in: MedlinePlus

Pharmacokinetic properties of elvitegravir with and without ritonavir. Modified with permission from Iwamoto M, Kassahun K, Troyer MD, et al 2008. Lack of pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. J Clin Pharmacol. 48(2):209–214.
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f3-tcrm-5-331: Pharmacokinetic properties of elvitegravir with and without ritonavir. Modified with permission from Iwamoto M, Kassahun K, Troyer MD, et al 2008. Lack of pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. J Clin Pharmacol. 48(2):209–214.

Mentions: Elvitegravir is a modified quinolone antibiotic that is also a potent INSTI. Elvitegravir undergoes both oxidative metabolism by CYP3A4 and glucuronidation. It is a moderate inducer of CYP3A4 and significant drug-drug interactions may occur when other CYP3A4 inducers or inhibitors are concomitantly administered. In healthy volunteers, the plasma half-life was approximately 3 hours when the drug was given alone but half-life is significantly enhanced if an inhibitor of CYP3A4, such as ritonavir, is co-administered. When ritonavir is co-administered, steady state exposure and minimum plasma concentrations increase 20-fold and 90-fold, respectively and the plasma half-life increases to approximately 9 hours, which then potentially allows for once daily dosing (Figure 3). Absorption of elvitegravir is increased approximately 3-fold when the drug is co-administered with food. Because of the superior performance of the highest dose tested in the phase II trial, the drug is being developed as 150 mg twice daily administration with ritonavir 100 mg in treatment-experienced patients.24,25


Emerging role of integrase inhibitors in the management of treatment-experienced patients with HIV infection.

Katlama C, Murphy R - Ther Clin Risk Manag (2009)

Pharmacokinetic properties of elvitegravir with and without ritonavir. Modified with permission from Iwamoto M, Kassahun K, Troyer MD, et al 2008. Lack of pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. J Clin Pharmacol. 48(2):209–214.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2697544&req=5

f3-tcrm-5-331: Pharmacokinetic properties of elvitegravir with and without ritonavir. Modified with permission from Iwamoto M, Kassahun K, Troyer MD, et al 2008. Lack of pharmacokinetic effect of raltegravir on midazolam: in vitro/in vivo correlation. J Clin Pharmacol. 48(2):209–214.
Mentions: Elvitegravir is a modified quinolone antibiotic that is also a potent INSTI. Elvitegravir undergoes both oxidative metabolism by CYP3A4 and glucuronidation. It is a moderate inducer of CYP3A4 and significant drug-drug interactions may occur when other CYP3A4 inducers or inhibitors are concomitantly administered. In healthy volunteers, the plasma half-life was approximately 3 hours when the drug was given alone but half-life is significantly enhanced if an inhibitor of CYP3A4, such as ritonavir, is co-administered. When ritonavir is co-administered, steady state exposure and minimum plasma concentrations increase 20-fold and 90-fold, respectively and the plasma half-life increases to approximately 9 hours, which then potentially allows for once daily dosing (Figure 3). Absorption of elvitegravir is increased approximately 3-fold when the drug is co-administered with food. Because of the superior performance of the highest dose tested in the phase II trial, the drug is being developed as 150 mg twice daily administration with ritonavir 100 mg in treatment-experienced patients.24,25

Bottom Line: Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development.Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed.The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

View Article: PubMed Central - PubMed

Affiliation: Pierre et Marie Curie Université - Paris 6, Service de Maladies Infectieuses et Tropicales, Paris, France.

ABSTRACT
Integrase is an essential HIV-1-specific enzyme that is an active target for antiretroviral drug development. Recently, a new class of drugs that specifically inhibits strand transfer, one of the three steps of HIV integration into the host DNA, has been developed. Two drugs in this class have reached late stages of development for use in HIV-1 infected individuals: raltegravir, which has just been approved for use in treatment-experienced patients, and elvitegravir, currently in phase III trials. Both are potent with an IC(50) in the 30 nM range and active in vitro against wild type as well as in strains highly resistant to all other existing classes of drugs. Clinical trials in both treatment-naïve and -experienced patients have demonstrated raltegravir to be highly effective with an excellent tolerability profile and no specific clinical or metabolic side effects. Longer follow up is necessary to ensure this early safety profile is sustained. The rapid rate of viral decay observed with raltegravir challenges the current understanding of HIV-1 turnover and may open new strategies for long term treatment and management of infected patients.

No MeSH data available.


Related in: MedlinePlus