A Comprehensive Pharmacological and Clinical Review of Darunavir (DB01264)

Executive Summary

Darunavir is a second-generation, nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) that constitutes a critical component of modern antiretroviral therapy (ART). Identified by DrugBank ID DB01264 and CAS Number 206361-99-1, it was developed through a structure-based design approach to overcome the significant challenges of drug resistance that plagued first-generation PIs. Its mechanism of action involves potent inhibition of the HIV-1 protease enzyme, preventing the cleavage of viral Gag-Pol polyproteins and thereby halting the production of mature, infectious virions. A defining feature of Darunavir is its unique ability to form extensive hydrogen bonds with the highly conserved backbone of the protease active site, a property that confers an exceptionally high genetic barrier to resistance.

Clinically, Darunavir is never used alone. Due to extensive first-pass metabolism by the cytochrome P450 3A (CYP3A) enzyme system, it must be co-administered with a pharmacokinetic (PK) booster—either ritonavir or cobicistat. This boosting strategy dramatically increases its bioavailability and extends its half-life, allowing for once or twice-daily dosing. However, this reliance on potent CYP3A inhibition is also the source of its primary clinical limitation: a high potential for significant drug-drug interactions with a wide array of commonly prescribed medications.