Trastuzumab: Difference between revisions

Revision as of 16:39, 8 December 2010

Better Known as: Agenerase

Marketed By: GlaxoSmithKline
Major Indication: Human Immunodeficiency Virus Infection
Drug Class: HIV Protease Inhibitor
Date of FDA Approval (Discontinued): 1999 (2004)
2004 Sales: ~$50 Million
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.
The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information

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 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 , which contain the . These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Amprenavir 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.^[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

Pharmacokinetics

EGFR Inhibitor Pharmacokinetics^[3]
Parameter	Trastuzumab
T_max (hr)	1.7
C_max (ng/ml)	203000
Bioavailability (%)
T_1/2 (days)	27
AUC (ug/ml/hr)	45036
Clearance (L/h)	.009
Dosage (mg)	250
Metabolism

References

↑ 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
↑ Flexner C, Bate G, Kirkpatrick P. Tipranavir. Nat Rev Drug Discov. 2005 Dec;4(12):955-6. PMID:16370086 doi:10.1038/nrd1907
↑ 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

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David Canner, Joel L. Sussman, Alexander Berchansky

[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

[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

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 {| class="wikitable" border="1" width="52%" 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 [[Pharmaceutical_Drugs#Pharmacokinetics_Translated|Pharmacokinetics]]<ref>DOI: 10.1200/JCO.2003.12.109</ref>
 |-
 ! Parameter
@@ Line 24: / Line 24: @@
 |-
 ! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)
-!
+! 1.7
 |-
 ! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)
-!
+! 203000
 |-
 ! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
 !
 |-
-! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
+! [[Pharmaceutical_Drugs#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)
-!
 |-
-! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
+! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ug/ml/hr)
-!
+! 45036
 |-
 ! [[Pharmaceutical_Drugs#Clearance_.28Cl.29|Clearance]] (L/h)
-!
+! .009
 |-
 ! Dosage (mg)
-!
+! 250
 |-
 ! Metabolism