Table 2.
Actions of ritonavir (RTV) and cobicistat (COBI).
| COBI | RTV |
|---|---|
| Similar Actions | |
| Potency on CYP 3A4 [137]. At therapeutic conc., inhibitory effect on the hepatic organic anions’ transporters of OATP polypeptides and MATE1 [116]. Inhibitory effect on the intestinal transporters P-gp and BCRP, thus increasing the absorption of co-administered substances [138]. Determine a slight increase in SCR and an associated decrease in glomerular filtration rate (reported in patients with RTV or COBI regimen included), mainly due to the inhibition of CR secretion, by inhibition of MATE1, and not due to impaired liver function [116,120,139,140]. Activate more or less PXR (which regulates the expression of various enzymes that metabolize drug substances) [142]. | |
| Different Actions | |
| More selective, at clinically relevant conc. [139]. No inhibitory effects on CYP 2C8 and slightly inhibits CYP 2D6 [138]. Increases SCR conc. (higher SCR levels than in patients with RTV-containing regimens) [116,120,139,140]. Active transporter in tubular cells, with OCT2; higher SCR levels mentioned above are explained by the fact that COBI preferentially accumulates in tubular cells and reaches conc. capable of inhibiting MATE1 [53,141]. Limited effect on PXR, being unlikely to have an enzymatic induction effect on drug metabolism [143,144,145] Less pill burden (available at single tablet regimen) [146]. Neutral effects on serum lipids [146]. Higher risk of DDIs in association with antithrombotic [146]. Contraindicated in HIV-infected pregnant women [146]. |
Activates PXR and induces CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation enzymes [143,144,145]. Higher potency for CYP 3A inhibition [136,137,146]. Fine tuning of individualized ARV regimens in patients with polytherapy [146]. Detrimental effects on serum lipids [146]. Higher risk of DDIs with non-CYP 3A substrates (considering party drugs as well) [146]. Recommended in HIV-infected pregnant women [146]. |
Legend: ARV—antiretroviral; BCRP—breast cancer resistance protein; COBI—cobicistat; conc—Concentration; CR—creatinine; CYP—cytochrome; DDI—drug-drug interaction; MATE—multidrug and toxin extrusion (a transporter involved in the tubular secretion of creatinine); OATP—organic anion transport protein; OCT2—organic cation transporter; P-gp—P-glycoprotein; PXR—pregnane X receptor (regulates the expression of various enzymes that metabolize drug substances); RTV—ritonavir; SCR—serum creatinine.