Lapatinib - Revision history

Joel L. Sussman at 17:13, 16 January 2017

Joel L. Sussman — Mon, 16 Jan 2017 17:13:38 GMT

←Older revision		Revision as of 17:13, 16 January 2017
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-	<StructureSection load='' size='~~350~~' side='right' scene='Lapatinib/Lapatinib/2' caption='Lapatinib, also known as Tykerb ([[3bbt]])'>	+	<StructureSection load='' size='450' side='right' scene='Lapatinib/Lapatinib/2' caption='Lapatinib, also known as Tykerb ([[3bbt]])'>
	__TOC__		__TOC__
	===Better Known as: Tykerb===		===Better Known as: Tykerb===

Joel L. Sussman at 12:22, 15 January 2017

Joel L. Sussman — Sun, 15 Jan 2017 12:22:20 GMT

←Older revision		Revision as of 12:22, 15 January 2017
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-	<~~applet~~ load="" size=~~"480" color~~=~~"" frame="true" spin="on" Scene~~ ="Lapatinib/Lapatinib/2~~" align="right"~~ caption="Lapatinib, also known as Tykerb ([[3bbt]])"/>	+	<StructureSection load='' size='350' side='right' scene='Lapatinib/Lapatinib/2' caption='Lapatinib, also known as Tykerb ([[3bbt]])'>
		+	__TOC__
	===Better Known as: Tykerb===		===Better Known as: Tykerb===
	* Marketed By: GlaxoSmithKline		* Marketed By: GlaxoSmithKline
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	</tr>		</tr>
	</table>		</table>
-		+	</StructureSection>
	===References===		===References===
	<references/>		<references/>
	__NOEDITSECTION__		__NOEDITSECTION__
-	__NOTOC__

David Canner at 18:10, 9 December 2010

David Canner — Thu, 09 Dec 2010 18:10:50 GMT

←Older revision		Revision as of 18:10, 9 December 2010
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	* Date of FDA Approval (Expiration): 2007 (2017)		* Date of FDA Approval (Expiration): 2007 (2017)
	* 2009 Sales (Projected Peak): $150 Million ($4.5 Billion)<ref>http://money.cnn.com/2006/06/03/news/companies/glaxo_breastcancer/index.htm</ref>		* 2009 Sales (Projected Peak): $150 Million ($4.5 Billion)<ref>http://money.cnn.com/2006/06/03/news/companies/glaxo_breastcancer/index.htm</ref>
-	* Importance: It is one of the newest treatments for cancer. Complaints over the high cost ($22,000) for a treatment course which only prolongs survival in breast cancer patients by less than 2 months. It is particularly effective against HER2-positive breast cancer.	+	* Importance: It is one of the newest treatments for cancer. Complaints over the high cost ($22,000) for a treatment course which only prolongs survival in breast cancer patients by less than 2 months. It is particularly effective against HER2-positive breast [[cancer]].
	* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders		* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders

David Canner at 13:41, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:41:44 GMT

←Older revision		Revision as of 13:41, 9 December 2010
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	[[EGFR\|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer\|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication\|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>		[[EGFR\|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer\|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication\|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>

-	===Pharmacokinetics~~<ref>[[TKI References]]</ref>~~===	+	===Pharmacokinetics===
	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">		<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">
	<tr>		<tr>

David Canner at 13:41, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:41:17 GMT

←Older revision		Revision as of 13:41, 9 December 2010
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	[[EGFR\|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer\|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication\|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>		[[EGFR\|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer\|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication\|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>

-	===Pharmacokinetics<ref>[[TKI References]]===	+	===Pharmacokinetics<ref>[[TKI References]]</ref>===
	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">		<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">
	<tr>		<tr>

David Canner at 13:41, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:41:07 GMT

←Older revision		Revision as of 13:41, 9 December 2010
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	[[EGFR\|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer\|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication\|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>		[[EGFR\|Epidermal Growth Factor Receptors]] are overexpressed in many types of human [[Cancer\|carcinomas]] including lung, pancreatic, and breast cancer, and are often mutated. This overexpression leads to excessive activation of the anti-apoptotic [[Ras]] signalling cascade, resulting in uncontrolled [[DNA_Replication\|DNA synthesis]] and cell proliferation. Studies have revealed that the <scene name='Lapatinib/Egfr/1'>EGFR tyrosine kinase domain</scene> is responsible for activating this Ras signaling cascade. Upon binding ligands like Epidermal Growth Factor, EGFR dimerizes and autophosphorylates several tyrosine residues at its C-terminal domain. Upon phosphorylation, EGFR undergoes a significant conformational shift, revealing an additional binding site capable of binding and activating downstream signaling proteins.<ref>PMID:6090945</ref><ref>PMID:16729045</ref> Erlotinib inhibits the EGFR tyrosine kinase by <scene name='Lapatinib/Egfbb/1'>binding to the ATP-binding site</scene> located within the kinase domain. Residues Met 774, Leu 825, Val 707, Thr 835, Asp 836, Phe 837, Thr 771, Lys 726, Ala 724, & Leu 769 tightly bind the inhibitor in place. Unable to bind ATP, EGFR is incapable of autophosphorylating its C-terminal tyrosines, and the uncontrolled cell-proliferation signal is terminated.<ref>PMID:15284455</ref><ref>PMID:15374980</ref>

-	===Pharmacokinetics===	+	===Pharmacokinetics<ref>[[TKI References]]===
	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">		<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">
	<tr>		<tr>

David Canner at 13:32, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:32:04 GMT

←Older revision		Revision as of 13:32, 9 December 2010
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	<tr>		<tr>
	<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">		<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
-	<div style="~~overflow:auto;~~ height:100%; width: 100%">	+	<div style="height:100%; width: 100%">
	{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}		{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}
	</div>		</div>

David Canner at 13:31, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:31:37 GMT

←Older revision		Revision as of 13:31, 9 December 2010
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	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">		<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">
	<tr>		<tr>
-	<td style="vertical-align:top;border-width:0px; border-style:inset">	+	<td style="width:100%; vertical-align:top;border-width:0px; border-style:inset">
	<div style="overflow:auto; height:100%; width: 100%">		<div style="overflow:auto; height:100%; width: 100%">
	{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}		{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}

David Canner at 13:31, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:31:16 GMT

←Older revision		Revision as of 13:31, 9 December 2010
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	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">		<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">
	<tr>		<tr>
-	<td style="~~width:auto;~~ vertical-align:top;border-width:0px; border-style:inset">	+	<td style="vertical-align:top;border-width:0px; border-style:inset">
	<div style="overflow:auto; height:100%; width: 100%">		<div style="overflow:auto; height:100%; width: 100%">
	{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}		{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}

David Canner at 13:30, 9 December 2010

David Canner — Thu, 09 Dec 2010 13:30:39 GMT

←Older revision		Revision as of 13:30, 9 December 2010
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	===Pharmacokinetics===		===Pharmacokinetics===
-	~~{\| class~~="~~wikitable~~" ~~border~~="1" width="55%" style="~~text~~-align:~~center~~"	+	<table style="background: cellspacing="0px" align="" cellpadding="0px" width="50%">
-	\|-	+	<tr>
-	~~! colspan~~="~~4" align="center"\| EGFR Inhibitor [[Pharmacokinetics]] Comparison at Equivalent Dosages<ref>PMID~~:~~16609030</ref><ref>PMID~~:~~17482782</ref><ref>D. Smith et al. Br J Clin Pharmacol. 2009 April~~; ~~67(4)~~: ~~421–426.</ref~~>	+	<td style="width:auto; vertical-align:top;border-width:0px; border-style:inset">
-	\|-	+	<div style="overflow:auto; height:100%; width: 100%">
-	~~! Parameter~~	+	{{:Tyrosine Kinase Inhibitor Pharmacokinetics}}
-	~~! [[Erlotinib]]~~ <br/>~~(Tarceva)~~	+	</div>
-	~~! [[Gefitinib]]~~ <br/>~~(Iressa)~~	+	</td>
-	~~! [[Lapatinib]]~~ <br/>~~(Tykerb)~~	+	</tr>
-	\|-	+	</table>
-	~~! [[Pharmacokinetics#Tmax\|T<sub>max~~</~~sub~~>~~]] (hr)~~	+
-	~~! 2.0~~	+
-	~~! 5.4~~	+
-	~~! 4~~	+
-	\|-	+
-	~~! [[Pharmacokinetics#Cmax\|C<sub>max</sub>]] (ng/ml)~~	+
-	~~! 69.6~~	+
-	~~! 130~~	+
-	~~! 115~~	+
-	\|-	+
-	~~! [[Pharmacokinetics#Bioavailability_.28F.29\|Bioavailability]] (%)~~	+
-	~~! 99~~	+
-	~~! 59~~	+
-	~~! Variable~~	+
-	\|-	+
-	~~! [[Pharmacokinetics#Protein_Binding\|Protein Binding]] (%)~~	+
-	~~! 93~~	+
-	~~! 90~~	+
-	~~! 99~~	+
-	\|-	+
-	~~! [[Pharmacokinetics#Half_Life_.28T1.2F2.29\|T<sub>1/2</sub>]] (hr)~~	+
-	~~! 9.4~~	+
-	~~! 26.9~~	+
-	~~! 9.6~~	+
-	\|-	+
-	~~! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29\|AUC]] (ng/ml/hr)~~	+
-	~~! 20577~~	+
-	~~! 3850~~	+
-	~~! 1429~~	+
-	\|-	+
-	~~! Typical Dosage (mg)~~	+
-	~~! 150~~	+
-	~~! 250~~	+
-	~~! 100~~	+
-	\|-	+
-	~~! Metabolism~~	+
-	~~! Hepatic - (CYP3A4)~~	+
-	~~! Hepatic - (CYP3A4)~~	+
-	~~! Hepatic - (CYP3A4)~~	+
-	\|}	+

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