Trastuzumab: Difference between revisions

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New page: <applet load="" size="480" color="" frame="true" spin="on" Scene ="Amprenavir/Amprenavi/2" align="right" caption="Amprenavir, better known as Agenerase, (3nu4)"/> ===Better Known as...
 
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<applet  load="" size="480" color="" frame="true"  spin="on" Scene ="Amprenavir/Amprenavi/2" align="right" caption="Amprenavir, better known as Agenerase, ([[3nu4]])"/>
<StructureSection load='3be1' size='450' side='right' caption='Tastuzumab, better known as Herceptin, ([[3be1]])' scene='Trastuzumab/Trastuzumab/1'>
===Better Known as: Agenerase===
__TOC__
* Marketed By: GlaxoSmithKline<br />
===Better Known as: Herceptin===
* Major Indication: [[Human Immunodeficiency Virus]] Infection<br />
* Marketed By: Genentech<br />
* Drug Class: [[HIV Protease]] Inhibitor
* Major Indication: Breast [[Cancer]]<br />
* Date of FDA Approval (Discontinued): 1999 (2004) <br />
* Drug Class: Human [[Epidermal Growth Factor Receptor]] 2 (HER2) Inhibitor
* 2004 Sales: ~$50 Million
* Date of FDA Approval (Discontinued): 1998 (2015) <br />
* 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]].
* 2008 Sales: $4.75 Billion
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* Importance: It is a very effective treatment against HER2-positive metastatic breast [[cancer]] compared to other cancer therapies. Controversial due to its cost of nearly $100,000 per year. Is often pointed to as an example of the benefits of personalized medicine in which a patent's genetic profile is used to optimize their medication regimen.  
* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders


===Mechanism of Action===
===Mechanism of Action===
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>
[[Epidermal Growth Factor Receptor|Human Epidermal Growth Factor Receptor 2]] (HER2) is overexpressed in approximately 30% of breast [[Cancer|cancers]]. Upon receiving a mitogenic signal, HER2, located in the cell membrane, dimerizes and transfers signals to receptors within the cell. This activates different pathways including the [[PI3K]] pathway and MAPK pathway, promoting cellular survival and replication. Trastuzumab is a humanized [[monoclonal antibody]] <scene name='Trastuzumab/Trastuzumab_h/1'>that binds to the domain IV</scene> of the extracellular segment of the HER2 receptor. It has been suggested that Trastuzumab binding disrupts receptor dimerization, preventing the errant signal from being transfered. This ultimately causes cells to arrest druing the G1 phase of the cell cycle, halting cellular proliferation.<ref>PMID:14528282</ref> <scene name='Trastuzumab/Vouns/5'>The extremely precise binding interaction</scene> between the Trastuzumab [[antibody]] Fab and HER2 involves residues Arg 58, Arg 50, Tyr 33, Tyr 100, & Gly 99 on the heavy chain Fab, Thr 94, His 91, Tyr 92, Tyr 32, & Tyr 53 on the light chain Fab, and Glu 558, Gln 561, Asp 560, Phe 573, Lys 569, Pro 572, Pro 571, Lys 593, Cys 601, Cys 604 & Gln 602 on the HER2 polypeptide.  
 
===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]]


<scene name='81/816443/Cv/24'>The overview of the distinct epitopes of HuA21, Trastuzumab and Pertuzumab</scene>. HuA21, Trastuzumab and Pertuzumab are labelled and colored slate, magenta and cyan, respectively. The HER2 subdomains I, II, III and IV are colored red, green, blue and yellow, respectively.<ref>doi 10.1107/S2059798319006995</ref>
===Pharmacokinetics===
===Pharmacokinetics===
{| class="wikitable" border="1" width="52%" style="text-align:center"
{| class="wikitable" border="1" width="40%" style="text-align:center"
|-
|-
!  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>
!  colspan="12" align="center"| EGFR Inhibitor [[Pharmacokinetics]]<ref>DOI: 10.1200/JCO.2003.12.109</ref><ref> B. Leyland-Jones, et al. Pharmacologic insights into the future of trastuzumab. Annals of Oncology 12 (Suppl. I): S43-S47, 2001.</ref>
|-
|-
! Parameter
! Parameter
! [[Trastuzumab]]
! [[Trastuzumab]]
|-
|-
! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)  
! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr)  
!  
! 1.7
|-
|-
! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)  
! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml)  
!  
! 203000
|-
|-
! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%)
!  
! 54
|-
|-
! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (days)
!  
! 27
|-
|-
! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ug/ml/hr)
!  
! 45036
|-
|-
! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! [[Pharmacokinetics#Clearance_.28Cl.29|Clearance]] (L/h)
!
! .009
|-
! [[Pharmaceutical_Drugs#Clearance_.28Cl.29|Clearance]] (L/h)
!  
|-
|-
! Dosage (mg)
! Dosage (mg)
!  
! 250
|-
|-
! Metabolism
! Metabolism
!  
! Unknown
|}
|}
 
</StructureSection>
===References===
===References===
<references/>
<references/>
__NOEDITSECTION__
__NOEDITSECTION__
__NOTOC__

Latest revision as of 16:30, 15 June 2022

Better Known as: Herceptin

  • Marketed By: Genentech
  • Major Indication: Breast Cancer
  • Drug Class: Human Epidermal Growth Factor Receptor 2 (HER2) Inhibitor
  • Date of FDA Approval (Discontinued): 1998 (2015)
  • 2008 Sales: $4.75 Billion
  • Importance: It is a very effective treatment against HER2-positive metastatic breast cancer compared to other cancer therapies. Controversial due to its cost of nearly $100,000 per year. Is often pointed to as an example of the benefits of personalized medicine in which a patent's genetic profile is used to optimize their medication regimen.
  • See Pharmaceutical Drugs for more information about other drugs and disorders

Mechanism of Action

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in approximately 30% of breast cancers. Upon receiving a mitogenic signal, HER2, located in the cell membrane, dimerizes and transfers signals to receptors within the cell. This activates different pathways including the PI3K pathway and MAPK pathway, promoting cellular survival and replication. Trastuzumab is a humanized monoclonal antibody of the extracellular segment of the HER2 receptor. It has been suggested that Trastuzumab binding disrupts receptor dimerization, preventing the errant signal from being transfered. This ultimately causes cells to arrest druing the G1 phase of the cell cycle, halting cellular proliferation.[1] between the Trastuzumab antibody Fab and HER2 involves residues Arg 58, Arg 50, Tyr 33, Tyr 100, & Gly 99 on the heavy chain Fab, Thr 94, His 91, Tyr 92, Tyr 32, & Tyr 53 on the light chain Fab, and Glu 558, Gln 561, Asp 560, Phe 573, Lys 569, Pro 572, Pro 571, Lys 593, Cys 601, Cys 604 & Gln 602 on the HER2 polypeptide.

. HuA21, Trastuzumab and Pertuzumab are labelled and colored slate, magenta and cyan, respectively. The HER2 subdomains I, II, III and IV are colored red, green, blue and yellow, respectively.[2]

Pharmacokinetics

EGFR Inhibitor Pharmacokinetics[3][4]
Parameter Trastuzumab
Tmax (hr) 1.7
Cmax (ng/ml) 203000
Bioavailability (%) 54
T1/2 (days) 27
AUC (ug/ml/hr) 45036
Clearance (L/h) .009
Dosage (mg) 250
Metabolism Unknown

Tastuzumab, better known as Herceptin, (3be1)

Drag the structure with the mouse to rotate

References

  1. ↑ Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003 Sep 29;22(42):6570-8. PMID:14528282 doi:10.1038/sj.onc.1206779
  2. ↑ Wang Z, Cheng L, Guo G, Cheng B, Hu S, Zhang H, Zhu Z, Niu L. Structural insight into a matured humanized monoclonal antibody HuA21 against HER2-overexpressing cancer cells. Acta Crystallogr D Struct Biol. 2019 Jun 1;75(Pt 6):554-563. doi:, 10.1107/S2059798319006995. Epub 2019 May 31. PMID:31205018 doi:http://dx.doi.org/10.1107/S2059798319006995
  3. ↑ Leyland-Jones B, Gelmon K, Ayoub JP, Arnold A, Verma S, Dias R, Ghahramani P. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003 Nov 1;21(21):3965-71. Epub 2003 Sep 24. PMID:14507946 doi:10.1200/JCO.2003.12.109
  4. ↑ B. Leyland-Jones, et al. Pharmacologic insights into the future of trastuzumab. Annals of Oncology 12 (Suppl. I): S43-S47, 2001.

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David Canner, Joel L. Sussman, Alexander Berchansky
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