Ritonavir
Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS.[4][5][6] This combination treatment is known as highly active antiretroviral therapy (HAART).[6] Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors.[6][7] It may also be used in combination with other medications to treat hepatitis C and COVID-19.[8][9] It is taken by mouth.[6] Tablets of ritonavir are not bioequivalent to capsules, as the tablets may result in higher peak plasma concentrations.[6]
For nirmatrelvir combined with ritonavir (sold under the brand name Paxlovid), see Nirmatrelvir/ritonavir.Clinical data
Norvir
RTV
- AU: B3
98–99%
3–5 hours
Mostly fecal
C37H48N6O5S2
720.95 g·mol−1
Common side effects of ritonavir include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[6] Serious side effects include liver complications, pancreatitis, allergic reactions, and arrythmias.[6] Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[6] At low doses, it is considered to be acceptable for use during pregnancy.[10] Ritonavir is of the protease inhibitor class.[6] However, it is also commonly used to inhibit the enzyme that metabolizes other protease inhibitors.[11] This inhibition allows lower doses of these latter medications to be used.[11]
Ritonavir was patented in 1989 and came into medical use in 1996.[12][13] It is on the World Health Organization's List of Essential Medicines.[14][15] Ritonavir capsules were approved as a generic medication in the United States in 2020.[16]
Polymorphism and temporary market withdrawal[edit]
Ritonavir was originally dispensed as a capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I.[50] However, like many drugs, crystalline ritonavir can exhibit polymorphism, i.e., the same molecule can crystallize into more than one crystal type, or polymorph, each of which contains the same repeating molecule but in different crystal packings/arrangements. The solubility and hence the bioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.[51]
During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,[52] more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market.[51] As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II, the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir; and indeed, form II was found in production lines, effectively halting ritonavir production.[50] Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension. It has been estimated that Abbott lost more than US$250 million as a result, and the incident is often cited as a high-profile example of disappearing polymorphs.[53]
The company's research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap. In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration.[54] Ritonavir tablets produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010.[55]
Society and culture[edit]
Economics[edit]
In 2003, Abbott (AbbVie, Inc.) raised the price of a Norvir course from US$1.71 per day to US$8.57 per day, leading to claims of price gouging by patients' groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004, that it lacked the legal right to allow generic production of Norvir.[56]