Nelfinavir (DB00220): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Nelfinavir, marketed under the brand name Viracept, is a first-generation, orally bioavailable, nonpeptidic human immunodeficiency virus (HIV) protease inhibitor (PI). It was a cornerstone of highly active antiretroviral therapy (HAART) following its landmark U.S. Food and Drug Administration (FDA) approval in 1997. As a potent competitive inhibitor of HIV-1 and HIV-2 protease, Nelfinavir's mechanism of action involves preventing the proteolytic cleavage of viral Gag-Pol polyproteins, a critical step in the viral life cycle. This inhibition results in the production of immature, non-infectious virions, thereby halting viral propagation. In combination with nucleoside reverse transcriptase inhibitors (NRTIs), Nelfinavir demonstrated the ability to produce substantial and sustained reductions in viral load and significant increases in CD4+ cell counts in both treatment-naïve and treatment-experienced patient populations.

The clinical utility of Nelfinavir is defined by a complex pharmacokinetic profile, characterized by a critical food effect for absorption, extensive hepatic metabolism by cytochrome P450 (CYP) isoenzymes CYP3A4 and CYP2C19, and a relatively short terminal half-life of 3.5 to 5 hours. Its safety profile is marked by a high incidence of gastrointestinal side effects, most notably diarrhea, and the potential for class-wide metabolic complications such as hyperglycemia and lipodystrophy. Furthermore, its potent inhibition of the CYP3A4 enzyme results in numerous clinically significant drug-drug interactions, a factor that complicates its use in patients on polypharmacy and has contributed to its decline in clinical practice.