Amprenavir

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(New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="" align="right" caption="Amprenavir, better known as Aptivus, (2o4p)"/> ===Better Known as: === * Marketed By: Gla...)
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<applet load="" size="480" color="" frame="true" spin="on" Scene ="" align="right" caption="Amprenavir, better known as Aptivus, ([[2o4p]])"/>
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<StructureSection load='' size='340' side='right' caption='Amprenavir, better known as Agenerase, ([[3nu4]])' scene='Amprenavir/Amprenavi/2'>
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===Better Known as: ===
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===Better Known as: Agenerase===
* Marketed By: GlaxoSmithKline<br />
* Marketed By: GlaxoSmithKline<br />
* Major Indication: [[Human Immunodeficiency Virus]] Infection<br />
* Major Indication: [[Human Immunodeficiency Virus]] Infection<br />
* Drug Class: [[HIV Protease]] Inhibitor
* Drug Class: [[HIV Protease]] Inhibitor
* Date of FDA Approval (Discontinued): 1999 (2004) <br />
* Date of FDA Approval (Discontinued): 1999 (2004) <br />
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* 2009 Sales: N/A
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* 2004 Sales: ~$50 Million
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* Importance: It was the ninth [[HIV Protease]] inhibitor approved by the FDA for treatment of HIV. It is a very potent inhibitor, and is often recommended for patients who have become resistant to other treatments, but also has a relatively harsh side-effect profile.
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* Importance: It was the first [[HIV Protease]] inhibitor which required only twice-a-day dosing as opposed to every 8 hours. It was replaced by a longer acting prodrug version called [[Fosamprenavir]].
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* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
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* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.
===Mechanism of Action===
===Mechanism of Action===
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When [[HIV]] infects a host, it directs the synthesis of several polyproteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by [[HIV Protease]]. The subunits of <scene name='Tipranavir/Prot/1'>HIV Protease</scene> come together to form a catalytic tunnel capable of binding the nascent peptides and cleaving them into their mature form. Within this tunnel lies <scene name='Tipranavir/Cat/3'>two Asp-Thr-Gly conserved sequences</scene>, which contain the <scene name='Tipranavir/Catas/1'>catalytic Asp residues</scene>. These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Indinavir <scene name='Tipranavir/Bound/1'>binds with great specificity</scene> to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their infectuous form, HIV is unable to mature and proliferate, allowing the patients immune system to fight off the infection more easily.<ref>PMID:1799632</ref><ref>doi:10.1038/nrd1907</ref>
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When [[HIV]] first infects someone, it directs the synthesis of several polyproteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by [[HIV Protease]]. The subunits of <scene name='Amprenavir/Protease/1'>HIV Protease</scene> come together to form a catalytic tunnel capable of tightly binding the nascent peptides and cleaving them into their mature, infectious form. Within this tunnel lies <scene name='Amprenavir/Proteasec/1'>two Asp-Thr-Gly conserved sequences</scene>, which contain the <scene name='Amprenavir/Proteasecas/2'>catalytic Asp residues</scene>. These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Amprenavir <scene name='Amprenavir/Bound/1'>binds specifically</scene> to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their infectious form, HIV is unable to mature and proliferate, allowing the patients immune system to fight off the infection more easily.<ref>PMID:1799632</ref><ref>doi:10.1038/nrd1907</ref>
===Drug Resistance===
===Drug Resistance===
The biggest difficulty with treating [[HIV]] is the rapidity at which it mutates and becomes resistant to treatments. To view a comprehensive and interactive analysis of the mutations which confer drug resistance to [[HIV Protease]], See: [[HIV Protease Inhibitor Resistance Profile]]
The biggest difficulty with treating [[HIV]] is the rapidity at which it mutates and becomes resistant to treatments. To view a comprehensive and interactive analysis of the mutations which confer drug resistance to [[HIV Protease]], See: [[HIV Protease Inhibitor Resistance Profile]]
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</StructureSection>
===Pharmacokinetics===
===Pharmacokinetics===
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{| class="wikitable" border="1" width="52%" style="text-align:center"
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<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">
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|-
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<tr>
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! colspan="12" align="center"| HIV Protease Inhibitor [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]]<ref>PMID:20400409</ref><ref>Ferry et al, United States Patent US6147095, Pharmacia & Upjohn Company.</ref><ref>L. Veronese et al. Single-Dose Pharmacokinetics of Amprenavir, a Human Immunodeficiency Virus Type 1 Protease Inhibitor, in Subjects with Normal or Impaired Hepatic Function. Antimicrob Agents Chemother. 2000 April; 44(4): 821–826.</ref><ref>J. Ford, et al. Intracellular and Plasma Pharmacokinetics of Saquinavir-Ritonavir, Administered at 1,600/100 Milligrams Once Daily in Human Immunodeficiency Virus-Infected Patients. Antimicrob Agents Chemother. 2004 July; 48(7): 2388–2393.</ref><ref>PMID:10620574</ref><ref>PMID:16086644</ref><ref>PMID:19131522</ref><ref>PMID: 10952482</ref><ref>PMID:16338276</ref><ref>PMID:19729375</ref><ref>PMID:12668574</ref><ref>PMID:17255144</ref><ref>PMID:10858338</ref>
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<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
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|-
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<div style="height:100%; width: 100%">
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! Parameter
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{{:HIV Protease Inhibitor Pharmacokinetics}}
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! [[Ritonavir]]
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</div>
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! [[Tipranavir]]
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</td>
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! [[Indinavir]]
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</tr>
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! [[Saquinavir]]
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</table>
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! [[Amprenavir]]
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! [[Fosamprenavir]]
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! [[Lopinavir]]
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! [[Darunavir]]
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! [[Atazanavir]]
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! [[Nelfinavir]]
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|-
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! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
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! 4.4
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! ~3
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! 1.5
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! 3.7
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! .98
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! 1.5-4
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! 2
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! .5
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! 2-4
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! 3.1
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|-
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! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
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! 13120
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! 14600
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! 8100
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! 2297
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! 4901
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! 4820
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! 11.9
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! 2730
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! ~4393
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! 4701
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|-
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! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
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! --
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! --
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! 65
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! 4
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! --
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! --
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! --
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! --
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! 68
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! 20-80
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|-
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! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
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! 99
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! >99
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! 61
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! 98
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! 90
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! 90
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! 99
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! 95
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! 86
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! 98
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|-
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! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
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! 4.8
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! 4.2
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! 1.2
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! 4.5
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! 5.5
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! 7.7
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! 6.1
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! 29.4
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! 5.3
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! 3.3
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|-
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! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
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! 128100
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! 46500
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! 20900
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! 13467
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! 11999
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! 35000
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! 117600
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! 4746
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! ~26045
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! 31906
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|-
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! [[Pharmaceutical_Drugs#Clearance_.28Cl.29|Clearance]] (L/h)
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! ~8.4
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! 32.4
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! 49.5
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! 36.7
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! 56.8
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! 84.4
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! 1.7
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! 32.8
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! 13.6
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! 37.3
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|-
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! Dosage (mg)
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! 600
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! 600
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! 800
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! 1000
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! 600
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! 1400
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! 280
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! 400
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! 400
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! 1250
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|-
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! Metabolism
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! Hepatic (CYP3A4 & CYP2C19)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4 & CYP3A5)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4)
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! Hepatic (CYP3A4)
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|}
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===References===
===References===

Current revision

Amprenavir, better known as Agenerase, (3nu4)

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Pharmacokinetics

HIV Protease Inhibitor Pharmacokinetics
Parameter Ritonavir Tipranavir Indinavir Saquinavir Amprenavir Fosamprenavir Lopinavir Darunavir Atazanavir Nelfinavir
Tmax (hr) 4.4 ~3 1.5 3.7 .98 1.5-4 2 .5 2-4 3.1
Cmax (ng/ml) 13120 14600 8100 2297 4901 4820 11.9 2730 ~4393 4701
Bioavailability (%) -- -- 65 4 -- -- -- -- 68 20-80
Protein Binding (%) 99 >99 61 98 90 90 99 95 86 98
T1/2 (hr) 4.8 4.2 1.2 4.5 5.5 7.7 6.1 29.4 5.3 3.3
AUC (ng/ml/hr) 128100 46500 20900 13467 11999 35000 117600 4746 ~26045 31906
Clearance (L/h) ~8.4 32.4 49.5 36.7 56.8 84.4 1.7 32.8 13.6 37.3
Dosage (mg) 600 600 800 1000 600 1400 280 400 400 1250
Metabolism Hepatic (CYP3A4 & CYP2C19) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4 & CYP3A5) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4) Hepatic (CYP3A4)

For Pharmacokinetic Data References, See: References

References

  1. ↑ Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ. The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie. 1991 Nov;73(11):1391-6. PMID:1799632
  2. ↑ Flexner C, Bate G, Kirkpatrick P. Tipranavir. Nat Rev Drug Discov. 2005 Dec;4(12):955-6. PMID:16370086 doi:10.1038/nrd1907


Proteopedia Page Contributors and Editors (what is this?)

David Canner, Alexander Berchansky

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