Disease relevance of Aptivus

• Tipranavir inhibits broadly protease inhibitor-resistant HIV-1 clinical samples [1].
• Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir [2].
• Three HIV-2 isolates were selected for resistance to amprenavir (APV), nelfinavir (NFV), indinavir (IDV), and tipranavir (TPV) in cell culture [3].
• This review summarizes the pharmacokinetic interactions between tipranavir/ritonavir and 11 other antiretroviral medications and between tipranavir/ritonavir and drugs used to treat opportunistic infections such as fungal infections, antiretroviral-treatment-related conditions such as hyperlipidemia, and side effects such as diarrhea [4].

High impact information on Aptivus

• Virologic response rates to tipranavir decreased when the baseline phenotype for tipranavir had a greater than three-fold shift in the 50% effective concentration (EC50) from reference [5].
• How flexible is tipranavir in complex with the HIV-1 protease active site [6]?
• Susceptibility to PNU-140690 (Tipranavir) of human immunodeficiency virus type 1 isolates derived from patients with multidrug resistance to other protease inhibitors [7].
• The aim of our experiments was to investigate the genotypes and the in vitro phenotypes of drug resistance of PNU-140690 [7].
• PNU-140690 retains good antiviral activity in vitro in the presence of human plasma proteins, and preclinical pharmacokinetic studies revealed good oral bioavailability [8].

Chemical compound and disease context of Aptivus

• Antiviral activity of the dihydropyrone PNU-140690, a new nonpeptidic human immunodeficiency virus protease inhibitor [8].
• Phenotypic results showed that indinavir, saquinavir, lopinavir and tipranavir had full activity against wild-type HIV-2 [9].
• Fortunately, the drug interactions between tipranavir coadministered with ritonavir and other antiretroviral medications or with other medications commonly used in HIV therapy are well characterized [4].
• The Non-Peptidic HIV Protease Inhibitor Tipranavir and Two Synthetic Peptidomimetics (TS98 and TS102) Modulate Pneumocystis carinii Growth and Proteasome Activity of HEL299 Cell Line [10].

Biological context of Aptivus

• A 14-day dose-response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients [11].
• Tipranavir without ritonavir does not acutely induce peripheral insulin resistance in a rodent model [12].
• In contrast, for drugs such as lopinavir and tipranavir, which always are used boosted with low-dose ritonavir, combinations of multiple protease mutations rather than few specific changes seem to be necessary for causing significant drug resistance [13].

Anatomical context of Aptivus

• Tipranavir is excreted primarily in the feces, with minimal excretion in urine [14].

Associations of Aptivus with other chemical compounds

• Displaying high enzymatic inhibition (Ki = 8 pM), potent in vitro antiviral cell culture activity (IC90 = 100 nM), and a useful pharmacokinetic profile, PNU-140690E (Tipranavir disodium) has entered into clinical studies [15].
• The modelling of sparse plasma samples using a first order absorption and elimination monocompartmental model without time lag predicted higher tipranavir elimination half-life and volume of distribution in enfuvirtide takers [16].
• Transaminase elevation rates (6.5%) and clinical hepatic event rates (5.9 events/100 person exposure years) were lower in the tipranavir/ritonavir with enfuvirtide group than in the tipranavir/ritonavir without enfuvirtide group [17].

Gene context of Aptivus

• At the end of the selection experiments, viruses harbouring 10 mutations in the protease (L10F, I13V, V32I, L33F, M36I, K45I, I54V, A71V, V82L, I84V) as well as a mutation in the CA/SP1 gag cleavage site were selected and showed 87-fold decreased susceptibility to tipranavir [18].
• In vitro, tipranavir-resistant viruses had a reduced replicative capacity which could not be improved by the introduction of the CA/SP1 cleavage site mutation [18].

Analytical, diagnostic and therapeutic context of Aptivus

• However, individuals taking enfuvirtide with tipranavir were able to achieve greater than 1.5 log10 reductions in viral load from baseline out to 24 weeks even if they had five or more baseline PI mutations [5].
• HIV-1 genotypic and phenotypic data from phase II and III clinical trials of tipranavir with protease inhibitor-experienced patients were analyzed to determine the association of protease mutations with reduced susceptibility and virologic response to tipranavir [2].
• Determination of tipranavir in human plasma by reverse phase liquid chromatography with UV detection using photodiode array [19].
• Therefore, tipranavir may be an HIV-1 protease inhibitor for which therapeutic drug monitoring (TDM) may be helpful in optimizing outcomes [19].
• Tipranavir: a protease inhibitor for HIV salvage therapy [20].

References