Lopinavir: Difference between revisions

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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="" align="right" caption="Lopinavir, better known as Kaletra, ([[2q5k]])"/>
<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
Line 7: Line 7:
* 2007 Sales: $1.1 Billion
* 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: 17696512</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===

Latest revision as of 15:56, 11 January 2024

Better Known as: Kaletra

  • Marketed By: Abbott Laboratories
  • Major Indication: Human Immunodeficiency Virus Infection
  • Drug Class: HIV Protease Inhibitor
  • Date of FDA Approval (Patent Expiration): 2000 (2016)
  • 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.
  • See Pharmaceutical Drugs for more information about other drugs and diseases.

Mechanism of Action

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 come together to form a catalytic tunnel capable of binding the nascent peptides and cleaving them into their mature form. Within this tunnel lies , which contain the . These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Indinavir 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.[1][2]

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

Lopinavir, better known as Kaletra, (2q5k)

Drag the structure with the mouse to rotate

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. ↑ Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Nathans RS, Schiffer CA, Rana TM. Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2' ligands in pseudosymmetric dipeptide isosteres. J Med Chem. 2007 Sep 6;50(18):4316-28. Epub 2007 Aug 16. PMID:17696512 doi:10.1021/jm070284z


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David Canner, Alexander Berchansky
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