Pharmacology Of Darunavir

Indication	Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.
Pharmacodynamics	Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. In studies, the drug, co-administered with ritonavir in combination therapy, significantly reduced viral load and increased CD4 cell counts in this treatment-experienced patient population (Tibotec, 2006, Product Monograph, Prezista 2006). Darunavir is used as an adjunct therapy with low dose ritonavir, which inhibits cytochrome P450 3A (CYP3A) which increases the bioavailability and half life of darunavir.
Mechanism of action	Darunavir is a HIV protease inhibitor which prevents HIV replication by binding to the enzyme's active site, thereby preventing the dimerization and the catalytic activity of the HIV-1 protease. Darunavir selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Structual analyses suggests that the close contact that darunavir has with the main chains of the protease active site amino acids (Asp-29 and Asp-30) is an important contributing factor to its potency and wide spectrum of activity against multi-protease inhibitor resistant HIV-1 variants. Darunavir can also adapt to the changing shape of a protease enzyme because of its molecular flexibility. Darunavir is known to bind to two distinct sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer.
Absorption	The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.
Volume of distribution	Not Available
Protein binding	Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
Metabolism	Hepatic. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A.
Route of elimination	Darunavir is primarily metabolized by CYP3A. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after single dose administration of 400 mg 14C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir was recovered in the feces and urine, respectively.
Half life	The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir.
Clearance	32.8 L/hr [Healthy volunteers receiving intravenous administration of 400 mg of darunavir] 5.9 L/hr [Healthy volunteers receiving intravenous administrations of 400 mg of darunavir and 100 mg of ritonavir twice daily]
Toxicity	Not Available