HIV Protease Inhibitor

Products

Most HIV protease inhibitors are commercially available in tablet or capsule form. In addition, a few liquid dosage forms are available for ingestion. Saquinavir (Invirase) was the first to be lanicized in 1995.

Structure and properties

The first HIV protease inhibitors were modeled on the natural peptide substrate of the HIV protease. The protease “cuts” between phenylalanine and proline. These agents therefore have a peptide-like structure (peptidomimetics). One problem with peptidomimetics is their low bioavailability. For saquinavir, for example, it is only 4%.

Effects

HIV protease inhibitors (ATC J05AE) have antiviral properties against HIV. The effects are due to inhibition of HIV protease. This enzyme is a homodimer consisting of two identical subunits of 99 amino acids each. It plays a central role in the maturation and replication of HIV. Aspartyl protease cleaves the Gag and GagPol polyprotein and contributes significantly to the formation of mature and infectious viral particles. Figure 2 shows the binding of an HIV protease inhibitor to the Active Site of the viral enzyme.

Indications

For treatment of HIV infection as part of combination antiretroviral therapy (HAART).

Dosage

According to the SmPC. While earlier agents had to be taken several times a day, products are now on the market that are administered only once or twice a day. Most protease inhibitors are taken with a pharmacokinetic booster (enhancer). This is a CYP inhibitor such as ritonavir or cobicistat, which inhibits the metabolic breakdown of the drug. Currently, low-dose ritonavir, which is itself a protease inhibitor, is most commonly used.

Active Ingredients

1st generation (1995-1997):

2nd generation (1999-2003):

3rd generation (2005-2006):

Contraindications

Contraindications include:

  • Hypersensitivity
  • Hepatic insufficiency
  • T.T. renal insufficiency
  • Combination with certain drugs

Full precautions can be found in the drug label.

Interactions

HIV protease inhibitors are usually substrates of CYP3A and have a high potential for drug-drug interactions with CYP substrates, inhibitors, and inducers. This is also because they are additionally combined with a CYP inhibitor. Furthermore, active ingredients are themselves CYP inhibitors and inducers and may therefore affect the pharmacokinetics of other drugs.

Adverse effects

Common side effects include digestive disturbances such as diarrhea, nausea and vomiting, headache, rash, weakness, and fatigue. Some protease inhibitors have liver-toxic properties. Numerous other side effects are possible. HIV protease inhibitors have been associated with fat redistribution (lipodystrophy). Finally, resistance to the agents is a problem.