Nelfinavir: Difference between revisions

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* 2004 Sales: $400 Million
* 2004 Sales: $400 Million
* Importance: Soon after its approval, it became the vest selling [[HIV Protease]] inhibitor monotherapy in the world.  
* Importance: Soon after its approval, it became the vest selling [[HIV Protease]] inhibitor monotherapy in the world.  
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information
* See [[Pharmaceutical Drugs]] for more information about other drugs and disorders.


===Mechanism of Action===
===Mechanism of Action===
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{| class="wikitable" border="1" width="52%" style="text-align:center"
{| 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"| HIV Protease Inhibitor [[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>
|-
|-
! Parameter
! Parameter
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! [[Nelfinavir]]
! [[Nelfinavir]]
|-
|-
! [[Pharmaceutical_Drugs#Tmax|T<sub>max</sub>]] (hr)  
! [[Pharmacokinetics#Tmax|T<sub>max</sub>]] (hr)  
! 4.4
! 4.4
! ~3
! ~3
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! 3.1
! 3.1
|-
|-
! [[Pharmaceutical_Drugs#Cmax|C<sub>max</sub>]] (ng/ml)  
! [[Pharmacokinetics#Cmax|C<sub>max</sub>]] (ng/ml)  
! 13120
! 13120
! 14600
! 14600
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! 4701
! 4701
|-
|-
! [[Pharmaceutical_Drugs#Bioavailability_.28F.29|Bioavailability]] (%)
! [[Pharmacokinetics#Bioavailability_.28F.29|Bioavailability]] (%)
! --
! --
! --
! --
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! 20-80
! 20-80
|-
|-
! [[Pharmaceutical_Drugs#Protein_Binding|Protein Binding]] (%)
! [[Pharmacokinetics#Protein_Binding|Protein Binding]] (%)
! 99
! 99
! >99
! >99
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! 98
! 98
|-
|-
! [[Pharmaceutical_Drugs#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! [[Pharmacokinetics#Half_Life_.28T1.2F2.29|T<sub>1/2</sub>]] (hr)
! 4.8
! 4.8
! 4.2
! 4.2
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! 3.3
! 3.3
|-
|-
! [[Pharmaceutical_Drugs#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! [[Pharmacokinetics#Area_Under_the_Curve_.28AUC.29|AUC]] (ng/ml/hr)
! 128100
! 128100
! 46500
! 46500
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! 31906
! 31906
|-
|-
! [[Pharmaceutical_Drugs#Clearance_.28Cl.29|Clearance]] (L/h)
! [[Pharmacokinetics#Clearance_.28Cl.29|Clearance]] (L/h)
! ~8.4
! ~8.4
! 32.4
! 32.4

Revision as of 14:31, 9 December 2010

Nelfinavir, better known as Viracept, (1ohr)

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Better Known as: Viracept

  • Marketed By: Agouron Pharmaceuticals (now part of Pfizer) & Roche
  • Major Indication: Human Immunodeficiency Virus Infection
  • Drug Class: HIV Protease Inhibitor
  • Date of FDA Approval (Patent Expiration): 1997 (2014)
  • 2004 Sales: $400 Million
  • Importance: Soon after its approval, it became the vest selling HIV Protease inhibitor monotherapy in the world.
  • See Pharmaceutical Drugs for more information about other drugs and disorders.

Mechanism of Action

When HIV infects a host, it directs the synthesis of several polyproteins during its maturation process. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by HIV Protease. The two subunits of come together to form a catalytic tunnel capable of binding the nascent peptides and cleaving them into their mature form. Buried within this tunnel lies , which contain the . These catalytic Asp residues carry out the hydrolytic cleavage of the viral polyproteins. Nelfinavir to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their functional 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]
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)

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. ↑ Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT. Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. Proteins. 2007 Apr 1;67(1):232-42. PMID:17243183 doi:10.1002/prot.21304
  3. ↑ 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
  4. ↑ Ferry et al, United States Patent US6147095, Pharmacia & Upjohn Company.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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


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