Darunavir

Better Known as: Prezista Marketed By: Tibotec Major Indication: Human Immunodeficiency Virus Infection Drug Class: HIV Protease Inhibitor Date of FDA Approval (Patent Expiration): 2006 (2012) 2009 Sales: $590 Million Importance: It is the Office of AIDS Research Advisory Council recommended treatment. It was designed to work against HIV Protease Inhibitor resistant strains of HIV and also has a reduced side effect profile compared to older treatments like Indinavir. Performed better than Kaletra in clinical trials. See Pharmaceutical Drugs for more information about other drugs and disorders. Mechanism of Action When Human Immunodeficiency Virus infects a host, 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 binding the nascent peptides and cleaving them into their mature form. Within this tunnel lies , which contain the . These catalytic Asp residues carry out the hydrolytic cleavage of the polyprotein. Atazanavir to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their appropriate form, HIV is unable to mature and proliferate, allowing the patients immune system to fight off the infection more easily. 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

spinqualitylabelsall models Darunavir, better known as Prezista, (3em6) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Pharmacokinetics

HIV Protease Inhibitor Pharmacokinetics 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) For Pharmacokinetic Data References, See: References