ネルフィナビル, FREE BASE

6

4.0

Slightly soluble

1.91e-03 g/L

Some degree of serum aminotransferase elevation occurs in a high proportion of patients taking nelfinavir containing antiretroviral regimens. Moderate-to severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in only 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent acute liver injury due to nelfinavir is rare. The few cases that have been reported have arisen after 1 to 8 weeks of starting nelfinavir, and the pattern of serum enzyme elevations has not been reported, but is likely to have been hepatocellular (Case 1). Signs of hypersensitivity (fever, rash, eosinophilia) can occur as can autoantibody formation but these features are not very prominent. The acute liver injury due to nelfinavir is usually self-limited, but it can be severe, and isolated cases of acute liver failure have been reported to the sponsor, although not in great detail. In HBV or HCV coinfected patients, some instances appear to be due to exacerbation of the underlying chronic liver disease, perhaps as a result of sudden immune reconstitution. Nelfinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors used to treat HIV infection.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

nelfinavir

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

Nelfinavir is a protease inhibitor with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs.

HIV viral protease is an important enzyme for HIV maturation and pathogenicity since HIV produces its structural and key proteins in the form of a polyprotein that needs to be cleaved by a protease. HIV protease is synthesized as part of the Gag-pol polyprotein, where Gag encodes for the capsid and matrix protein to form the outer protein shell, and Pol encodes for the reverse transcriptase and integrase protein to synthesize and incorporate its genome into host cells. The Gag-pol polyprotein undergoes proteolytic cleavage by HIV protease to produce 66 molecular species which will assume conformational changes to become fully active. Inhibition of protease, therefore, prevents HIV virion from fully maturing and becoming infective. Nelfinavir is a competitive inhibitor of the HIV protease by reversibly binding to the active site of the enzyme, preventing it from interacting with its substrate to produce mature and infectious viral particles.

Unchanged nelfinavir comprised 82-86% of the total plasma radioactivity after a single oral 750 mg dose of 14C-nelfinavir. In vitro, multiple cytochrome P-450 enzymes including CYP3A and CYP2C19 are responsible for the metabolism of nelfinavir. One major and several minor oxidative metabolites were found in plasma. The major oxidative metabolite has in vitro antiviral activity comparable to the parent drug.