Trastuzumab
|
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
| HIV Protease Inhibitor Pharmacokinetics[3][4][5][6][7][8][9][10][11][12][13][14][15] | |||||||||||
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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
- ↑ Goebel FD, MacGregor TR, Sabo JP, Castles M, Johnson PA, Legg D, McCallister S. Pharmacokinetic characterization of three doses of tipranavir boosted with ritonavir on highly active antiretroviral therapy in treatment-experienced HIV-1 patients. HIV Clin Trials. 2010 Jan-Feb;11(1):28-38. PMID:20400409 doi:10.1310/hct1101-28
- ↑ Ferry et al, United States Patent US6147095, Pharmacia & Upjohn Company.
- ↑ 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.
- ↑ 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.
- ↑ Remmel RP, Kawle SP, Weller D, Fletcher CV. Simultaneous HPLC assay for quantification of indinavir, nelfinavir, ritonavir, and saquinavir in human plasma. Clin Chem. 2000 Jan;46(1):73-81. PMID:10620574
- ↑ Fuster D, Clotet B. Review of atazanavir: a novel HIV protease inhibitor. Expert Opin Pharmacother. 2005 Aug;6(9):1565-72. PMID:16086644 doi:10.1517/14656566.6.9.1565
- ↑ Vermeir M, Lachau-Durand S, Mannens G, Cuyckens F, van Hoof B, Raoof A. Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects. Drug Metab Dispos. 2009 Apr;37(4):809-20. Epub 2009 Jan 8. PMID:19131522 doi:10.1124/dmd.108.024109
- ↑ von Moltke LL, Durol AL, Duan SX, Greenblatt DJ. Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole. Eur J Clin Pharmacol. 2000 Jun;56(3):259-61. PMID:10952482
- ↑ Mouly SJ, Matheny C, Paine MF, Smith G, Lamba J, Lamba V, Pusek SN, Schuetz EG, Stewart PW, Watkins PB. Variation in oral clearance of saquinavir is predicted by CYP3A5*1 genotype but not by enterocyte content of cytochrome P450 3A5. Clin Pharmacol Ther. 2005 Dec;78(6):605-18. PMID:16338276 doi:10.1016/j.clpt.2005.08.014
- ↑ Puthanakit T, van der Lugt J, Bunupuradah T, Ananworanich J, Gorowara M, Phasomsap C, Jupimai T, Boonrak P, Pancharoen C, Burger D, Ruxrungtham K. Pharmacokinetics and 48 week efficacy of low-dose lopinavir/ritonavir in HIV-infected children. J Antimicrob Chemother. 2009 Nov;64(5):1080-6. Epub 2009 Sep 2. PMID:19729375 doi:10.1093/jac/dkp322
- ↑ Burger D, Boyd M, Duncombe C, Felderhof M, Mahanontharit A, Ruxrungtham K, Ubolyam S, Stek M, Cooper D, Lange J, Phanupak P, Reiss P. Pharmacokinetics and pharmacodynamics of indinavir with or without low-dose ritonavir in HIV-infected Thai patients. J Antimicrob Chemother. 2003 May;51(5):1231-8. Epub 2003 Mar 28. PMID:12668574 doi:10.1093/jac/dkg198
- ↑ Stocker H, Herzmann C, Breske A, Kruse G, Berger M, Schulbin H, Hill A, Steinmuller J, Becker M, Arasteh K, Kurowski M. Saquinavir, nelfinavir and M8 pharmacokinetics following combined saquinavir, ritonavir and nelfinavir administration. J Antimicrob Chemother. 2007 Mar;59(3):560-4. Epub 2007 Jan 25. PMID:17255144 doi:10.1093/jac/dkl516
- ↑ Jackson KA, Rosenbaum SE, Kerr BM, Pithavala YK, Yuen G, Dudley MN. A population pharmacokinetic analysis of nelfinavir mesylate in human immunodeficiency virus-infected patients enrolled in a phase III clinical trial. Antimicrob Agents Chemother. 2000 Jul;44(7):1832-7. PMID:10858338