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Lopinavir: Difference between revisions

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New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="" align="right" caption="Lopinavir, better known as Kaletra, (1hsg)"/> ===Better Known as: Kaletra=== * Marketed B...
 
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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="" align="right" caption="Lopinavir, better known as Kaletra, ([[1hsg]])"/>
<StructureSection load='' size='340' side='right' caption='Lopinavir, better known as Kaletra, ([[2q5k]])' scene='Lopinavir/Lopinavir/1'>
===Better Known as: Kaletra===
===Better Known as: Kaletra===
* Marketed By: Abbott<br />
* Marketed By: Abbott Laboratories<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 (Patent Expiration): 2000 (2016) <br />
* Date of FDA Approval (Patent Expiration): 2000 (2016) <br />
* 2009 Sales: $200 Million
* 2007 Sales: $1.1 Billion
* Importance: Forms part of the Lopinavir & Ritonavir first-line therapy for HIV infections. Due to its low bioavilbility, it is sold as a co-formulation with [[Ritonavir]], which is a potent CYP3A4 inhibitor.  
* Importance: Forms part of the Lopinavir & Ritonavir first-line therapy for HIV infections. Due to its low bioavilbility, it is sold as a co-formulation with [[Ritonavir]], which is a potent CYP3A4 inhibitor.  
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* See [[Pharmaceutical Drugs]] for more information about other drugs and diseases.


===Mechanism of Action===
===Mechanism of Action===
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='Indinavir/Hiv_p/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='Indinavir/Cat/1'>two Asp-Thr-Gly conserved sequences</scene>, which contain the <scene name='Indinavir/Cat/2'>catalytic Asp residues</scene>. These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Indinavir <scene name='Indinavir/Indinavir/2'>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 appropriate 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>PMID:15066177</ref>
When [[HIV]] infects an individuals body, 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='Lopinavir/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='Lopinavir/Protca/1'>two Asp-Thr-Gly conserved sequences</scene>, which contain the <scene name='Lopinavir/Protcaas/1'>catalytic Asp residues</scene>. These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Indinavir <scene name='Lopinavir/Bound/1'>binds with great specificity</scene> to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to cleave the nascent proteins into their appropriate 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>PMID: 17696512</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]]
 
</StructureSection>
===Pharmacokinetics===
===Pharmacokinetics===
{| class="wikitable" border="1" width="52%" style="text-align:center"
<table style="background: cellspacing="0px" align="" cellpadding="0px" width="42%">  
|-
<tr>
!  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>
<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
|-
<div style="height:100%; width: 100%">
! Parameter
{{:HIV Protease Inhibitor Pharmacokinetics}}
! [[Ritonavir]]
</div>
! [[Tipranavir]]
</td>
! [[Indinavir]]
</tr>
! [[Saquinavir]]
</table>
! [[Amprenavir]]
! [[Fosamprenavir]]
! [[Lopinavir]]
! [[Darunavir]]
! [[Atazanavir]]
! [[Nelfinavir]]
|-
! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
! 4.4
! ~3
! 1.5
! 3.7
! .98
! 1.5-4
! 2
! .5
! 2-4
! 3.1
|-
! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
! 13120
! 14600
! 8100
! 2297
! 4901
! 4820
! 11.9
! 2730
! ~4393
! 4701
|-
! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
! --
! --
! 65
! 4
! --
! --
! --
! --
! 68
! 20-80
|-
! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
! 99
! >99
! 61
! 98
! 90
! 90
! 99
! 95
! 86
! 98
|-
! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! 4.8
! 4.2
! 1.2
! 4.5
! 5.5
! 7.7
! 6.1
! 29.4
! 5.3
! 3.3
|-
! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! 128100
! 46500
! 20900
! 13467
! 11999
! 35000
! 117600
! 4746
! ~26045
! 31906
|-
! [[Pharmaceutical_Drugs#Clearance_.28Cl.29|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)
|}


===References===
===References===

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

David Canner, Alexander Berchansky
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