Application of Ritonavir

Ritonavir (Ritonavire; 1,3-Thiazol-5-ylmethyl N-[(2S,3S,5S)- 3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate)  is an important active pharmaceutical ingredients[1]. A synthetic chemical available for oral use as soft capsules and a liquid formulation. It is now almost exclusively used as a pharmacokinetic enhancer to ‘boost’ the pharmacokinetic properties of HIV protease inhibitors in the treatment of HIV-1 infection in patients over 1 month in age. 

In addition, Norvir was launched in Germany, the UK and US for treatment of advanced HIV[2] in combination with antiretroviral nucleoside analogs in a record 72 days by the FDA. It is an inhibitor of HIV aspartic protease which is critical in the processing of a propeptide into the gag, gag-pol gene products and the protease itself. This inhibition results in the release of non-infectous immature virus particles. It is greater than 500-fold more selective for viral aspartic protease than the human version, has good oral bioavailability and may increase the bioavailability of other protease inhibitors. Ritonavir was able to increase the CD4 and CD8 lymphocyte count as well as reduce viral RNA. It is more potent than saqunavir and comparible in potency to zidovudine and lamivudine. 

Meanwhile, Ritonivir is an HIV protease inhibitor (EC50 = 25 nM) that also inhibits CYP3A4, the primary cytochrome P450 isoform that metabolizes protease inhibitors. Through CYP3A4 inhibition, low doses of ritonivir can reduce the metabolism of concomitantly administered protease inhibitiors, enhancing their bioavailability and efficacy. Although ritonavir (Norvir) is a potent inhibitor of HIV-1 and HIV-2 protease[3], it is not well tolerated in higher doses. It is mainly used in low doses to increase blood levels of other protease inhibitors and to extend their dosing interval. Ritonavir is more commonly associated with gastrointestinal side effects, altered taste sensation, paresthesias, and hypertriglyceridemia than are other protease inhibitors. Pancreatitis may occur in the presence or absence of hypertriglyceridemia.

References

[1] https://www.chemicalbook.com/ProductChemicalPropertiesCB0119429_EN.htm
[2] Sullivan A K, Nelson M R. Marked hyperlipidaemia on ritonavir therapy[J]. Aids, 1997, 11(7): 938-939.
[3] Walmsley S, Bernstein B, King M, et al. Lopinavir–ritonavir versus nelfinavir for the initial treatment of HIV infection[J]. New England Journal of Medicine, 2002, 346(26): 2039-2046

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