Protease inhibitors ritonavir

Fig. 7.3 Binding of the HIV protease inhibitor ritonavir. Amino acids highlighted in cyan are mutated in resistant strains of the virus and tend to occur at the extremities of the inhibitor (see color plates, p. XXXIII).

HIV-1 protease inhibitors Ritonavir Aquinavir Saquinavir Indinavir Nelfinavir... 

Cross-resistance between indinavir and HIV reverse transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been observed between indinavir and other HIV-protease inhibitors. 

As with other protease inhibitors, ritonavir will predominantly be used in combination regimens the ability of ritonavir (alone or in combinations) to modify clinical endpoints (e.g., time to first AlDS-defining illness or death) will be important in determining the ultimate role of this agent in HIV potential for drug interaction is troublesome as with other protease inhibitors, resistance has been problematic after several mo of treatment... 

Patel J, Buddha B, Dey S, Pal D, Mitra AK. In vitro interaction of the HIV protease inhibitor ritonavir with herbal constituents changes in P-gp and CYP3A4 activity. Am J Ther 2004 ll(4) 262-277. 

Saquinavir is available as Invirase, which is its hard gelatin form, and Forto-vase, which is its soft gelatin form. In combination with other antiretroviral agents and another protease inhibitor ritonavir, Invirase is recommended for the treatment of HIV infection, and due to its low bioavailability, considerably higher doses are recommended. The two preparations, Invirase and Fortovase, are not bioequivalent and could not be used interchangeably. Although Fortovase can be used as a sole protease inhibitor in a combination therapy, Invirase could be used only in combination with ritonavir. 

Olson, D.P., et al. 2002. The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1). AIDS 16 1743. 

The ability of lipid vehicles (either in the pharmaceutical formulation or in food) to enhance the absorption of lipophilic drugs has been well known for many years. Recently, successful bioavailability enhancement utilizing lipid-based formulations has been accomplished with the immunosuppressive agent cyclosporine A (Neoral, Novartis Pharmaceuticals Corporation, East Hanover, NJ), and for the two HIV protease inhibitors ritonavir (Norvir, Abbott Laboratories, IL) and saquinavir (Fortovase, Roche Pharmaceuticals, Nutley, NJ). Consequently, considerable interest in lipid-based formulations has been aroused. 

Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson O. Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization. Proc Natl Acad Sci 2003 100(5) 2180-2184. 

Hsu A, Granneman G, Cao G, et al. Pharmacokinetic interactions between two HIV-protease inhibitors, ritonavir and saquinavir. Clin Pharmacol Ther 1998 63 453-464. 

In an in vitro study of the effects of the HIV-1 protease inhibitors, ritonavir, indinavir, and saquinavir, which are metabolized by the liver CYP3A4, all three protease inhibitors inhibited methadone demethylation and buprenor-phine dealkylation in rank order of potency ritonavir > indinavir > saquinavir (53). Clinical studies are required to establish the further relevance of these observations. 

TOREMIFENE PROTEASE INHIBITORS -RITONAVIR t plasma concentrations of toremifene Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes by ritonavir Clinical relevance is uncertain. Necessaiy to monitor for clinical toxicities... 

CORTICOSTEROIDS PROTEASE INHIBITORS-RITONAVIR t plasma levels of betamethasone, dexamethasone, hydrocortisone, prednisolone and both inhaled and intranasal budesonide and fluticasone with ritonavir (with or without lopinavir) Inhibition of CYP3A4-mediated metabolism Monitor closely for signs of corticosteroid toxicity and immunosupression, and i dose as necessaiy. Consider using inhaled bedometasone... 

NSAIDs PROTEASE INHIBITORS Ritonavir t piroxicam levels Uncertain ritonavir is known to inhibit CYP2C9, for which NSAIDs are substrates Avoid co-administration... 

A 28-year-old woman was taking triple therapy for HIV infection, including the protease inhibitor ritonavir (35). 

Mueller BU, Nelson RP Jr, Sleasman J, Zuckerman J, Heath-Chiozzi M, Steinberg SM, Bahs FM, Brouwers P, Hsu A, Saulis R, Sei S, Wood LV, Zeichner S, Katz TT, Higham C, Aker D, Edgerly M, Jarosinski P, Serchuck L, Whitcup SM, Pizzuti D, Pizzo PA. A phase FII study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection. Pediatrics 1998 101(3 Pt 1) 335 3. 

The same data-interpretation strategy is applied by Gangl et al. [13] in a study on the metabolism of the HIV-protease inhibitors ritonavir and indinavir (see Figure 10.2c). After the in vitro generation by incubation with human liver microsomes, the metabolites were extracted by means of LLE. Gradient elution LC-MS on an ion-trap instrument was applied to search for possible metabolites, which were subsequently fragmented in time-scheduled triple-quadrapole MS-MS. 

HIV-protease inhibitors Ritonavir, saquinavir, indinavir, nelfinavir p-GP Mrp2... 

Indinavir (800 mg/t.i.d.) is an inhibitor of the HIV protease, which is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious viral particles. Cross-resistance between indinavir and HIV reverse-transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been noted between indinavir and other HIV protease inhibitors. Indinavir is metabolized in the liver, and seven metabolites have been identified, and 20% of indinavir is excreted unchanged in the urine. 

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