The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market. 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. 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 $250 million USD as a result, and the incident is often cited as a high-profile example of disappearing polymorphs.The companys 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. Ritonavir produced in a solid dispersion by melt-extrusion was found to remain in form I, and was re-introduced commercially in 2010. Society and culture
Economics
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.
The drug binds to and inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART. However, because of the general role of CYP3A4 in xenobiotic metabolism, dosing with ritonavir also affects the efficacy of numerous other medications, adding to the challenge of prescribing drugs concurrently. Pharmacodynamics and pharmacokinetics
The capsules of the medication do not have the same bioavailability as the tablets.Ritonavir was demonstrated to have an in vitro potency of EC50=0.02µM and highly sustained concentration in plasma after oral administration in several species. Chemistry
Ritonavir was initially derived from a moderately potent and orally bioavailable small molecule, A-80987. The P3 and P2′ heterocyclic groups of A-80987 were redesigned to create an analogue, now known as ritonavir, with improved pharmacokinetic properties to the original.Full details of the synthesis of ritonavir were first published by scientists from Abbott Laboratories. In the first step shown, an aldehyde derived from phenylalanine is treated with zinc dust in the presence of vanadium(III) chloride. This results in a pinacol coupling reaction which dimerizes the material to provide an intermediate which is converted to its epoxide and then reduced to (2S,3S,5S)-2,5-diamino-1,6-diphenylhexan-3-ol. Importantly, this retains the absolute stereochemistry of the amino acid precursor. The diamine is then treated sequentially with two thiazole derivatives, each linked by an amide bond, to provide ritonavir. History
Ritonavir is sold as Norvir by AbbVie, Inc..