Saquinavir with other protease inhibitors

Compared to baseline saquinavir pharmacokinetic parameters obtained in period 1, the use of garlic reduced the mean saquinavir area under the concentration-time curve (AUC) by 51%, and the maximum (Cmax) and minimum (Cmin) saquinavir concentrations by 54% and 49%, respectively. After a 10-day washout, the AUC, Cmax, and Cmin values were within a range of 60% to 70% of baseline values. The magnitude of the decline in concentration might result in therapeutic failure and viral rebound in patients with HIV. Based on the pharmacokinetic parameters obtained in period 3, it also appears that garlic might have a prolonged, albeit lesser, effect on saquinavir exposure. The effects of combined treatment with other protease inhibitors that are also potent cytochrome P-450 (CYP) enzymes modulators need to be further evaluated. 

Saquinavir substantially potentiates the effects of midazolam by raising its blood concentrations, and this suggests that a parallel interaction could occur with other protease inhibitors (and no doubt certain other benzodiazepines) in similar combinations (59). 

Eruptive angiolipomata occurred in a 49-year-old woman after she had taken stavudine 30 mg bd, lamivudine 150 mg bd, and saquinavir 600 mg 8-hourly for 3 months (11). This has also been reported with other protease inhibitors (12,13) and the mechanism is not known. In one case lipomata regressed after the introduction of indinavir (14). 

Rifampicin markedly reduces the levels of many of the protease inhibitors, and its use with unboosted protease inhibitors should be avoided, because of the risk of reduced antiviral efficacy and emergence of resistant viral strains. There are limited data to suggest that ritonavir as the sole protease inhibitor, or ritonavir used as a pharmacokinetic enhancer with other protease inhibitors such as saquinavir, can be used with rifampicin. However, further study has shown a high incidence of hepatotoxicity with saquinavir/ritonavir 1000/100 mg twice daily and rifampicin, and the manufacturers of ritonavir and saquinavir advise that these drugs should not be given together with rifampicin. Current UK guidelines state that, until more data are available, ritonavir-boosted protease inhibi-... 

In 1995 the FDA approved saquinavir, the first protease inhibitor, for use in combination with other nucleoside analogue medications. In 1999 a soft gel capsule formulation of saquinavir with considerably improved absorption characteristics was developed. Ritonavir and indinavir have been approved for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Nelfinavir is the first protease inhibitor labeled for use in children. Amprenavir is the newest of the protease inhibitors. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because the fat content may decrease the absorption of the drug. The most disturbing adverse reactions to protease inhibitors consist of the lipodystrophy syndrome with severe hyperlipidemia and unpredictable fat redistributions over the body... 

Amprenavir (Agenerase) is administered twice daily, providing the patient with an advantage over other protease inhibitors that must be taken more frequently (e.g., indinavir, saquinavir). Common side effects of am-... 

Saquinavir is subject to extensive first-pass metabolism by CYP3A4, and functions as a CYP3A4 inhibitor as well as a substrate thus, it should be used with the same precautions regarding drug-drug interactions as the other protease inhibitors. Coadministration with the CYP3A4 inhibitor ritonavir has been adopted by clinicians because inhibition of first-pass metabolism of saquinavir by ritonavir can result in higher—and thus more efficacious—levels of saquinavir (see Table 49-3 and Table 49-4). Liver function tests should be monitored if saquinavir is coadministered with delavirdine. 

The results of a questionnaire survey of 878 people with HIV infection treated with antiretroviral drugs also suggested that other protease inhibitors can cause arthralgia indinavir and the combination of ritonavir + saquinavir were particularly implicated (43). 

Gynecomastia has been reported in a series of men taking saquinavir (5). In these cases the association was clear (particularly since there was positive dechallenge), but this is a rare effect and has not previously been reported with either this or other protease inhibitors, although it has been associated with the nucleoside analogue reverse transcriptase inhibitor stavudine. 

Ritonavir (RTV) is also an inhibitor of HIV proteases, approved for use in combination with nucleoside analog, for the treatment of HIV-l infected adults, adolescents, and children. It is a potent CYP 3A4 inhibitor and is used at low doses to elevate plasma concentrations of other protease inhibitors being primarily metabolized by CYP 3A4. In combination with saquinavir, this type of interaction has proved favourable (28). The combination with nelfinavir showed much smaller effects on nelfinavir levels, but it appears to change in normal metabolizers the M8/nelfinavir concentration ratio from 0.3 to 0.6. In poor CYP 2C19 metaboliz-ers (-3-5% of Caucasians and African-Americans, -12-20% of Asians), ritonavir addition is not expected to have such an effect on the nelfinavir/M8 ratio (29). In addition, ritonavir induces CYP isoenzymes, so that the full effect of the nelfina-vir-ritonavir drug-drug interaction is considered stable after a treatment duration of 10-14 days (30). 

Nelflnavir markedly increases terfenadine levels, which is expected to increase the risk of QT prolongation and torsade de pointes arrhythmias. Other protease inhibitors are predicted to interact similarly with both terfenadine and astemizole, and concurrent use Is contraindicated. Ritonavir modestly increases cetirizine levels, and in vitro data suggests that saquinavir will have a similar effect, but this Is not considered to be clinically relevant. Based on in vitro data, ritonavir is predicted to markedly raise fexofenadine levels, but this may not be of any clinical relevance. 

In a placebo-controlled study in healthy subjects, efavirenz 600 mg once daily for 14 days reduced the steady-state AUC and maximum plasma level of maraviroc 100 mg twice daily by about 50%. Doubling the dose of maraviroc to 200 mg twice daily overcame this increase in metabolism, resulting in a minor 10% increase in AUC and 20% increase in maximum level, when compared with maraviroc 100 mg twice daily alone. Similarly, in another study, the AUC of a single 300-mg dose of maraviroc was about 50% lower in two groups of 8 patients one group taking efavirenz, lami vudine and zidovudine and the other taking efavirenz, didanosine and tenofovir. When efavirenz 600 mg daily was added to lopinavir/ritonavir 400/100 mg twice daily with maraviroc 300 mg twice daily, the increase in maraviroc AUC seen with these protease inhibitors , (p.780), was reduced from about 300% to about 150%, when compared with the AUC for maraviroc alone. Similarly, when efavirenz 600 mg daily was added to saquinavir/ritonavir 1000/100 mg twice daily with maraviroc 100 mg twice daily, the increase in maraviroc AUC seen with these protease inhibitors was reduced from 877% to 400%, when compared with the AUC for maraviroc alone. ... 

In general, efavirenz and nevirapine decrease the levels of protease inhibitors, whereas delavirdine increases them. Ritonavir is sometimes used to elevate the levels of other protease inhibitors when efavirenz or nevirapine are required. Amprenavir and nelflnavir decrease the levels of delavirdine. Most protease inhibitors do not appear to affect the levels of efavirenz or nevirapine. There is some evidence of increased adverse effects with antiviral doses of ritonavir and efavirenz, or saquinavir and delavirdine, including raised liver enzymes. Note that NNRTIs are not given with protease inhibitors in current first-line regimens for HIV infection either an NNRTI or protease inhibitors are combined with dual NRTIs. 

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. 

As with all viruses, HIV relies on a viral protease to properly cleave viral proteins in preparation for creating new viral particles. Drugs that block HIV protease are known as protease inhibitors (PI). The first HIV PI was saquinavir (Invirase, A.167), which was approved by the FDA in 1995 (Figure A.47). Pis therefore trailed NRTIs by nearly 10 years. Other Pis have since been approved. The most recently approved PI is darunavir (Prezista, A.168), which reached the market in 2006. 

The findings of this study were consistent with the surrogate marker studies of the protease inhibitor saquinavir (Markowitz et al., 1995 Danner et al., 1995 Collier et al., 1996) and subsequent studies of indinavir (Hammer et al., 1997 Hirsch et al, 1999 Gulick et al., 1997). This study was different from many others that will be cited, and the clinical situation requires some explanation. First, this study did not attempt to compare strategies of multiple ART combinations. Rather, it demonstrated the value of adding a protease inhibitor various ART regimens. In addition to the study design, the patient population was critical for the conclusions of the study. Patients with the most profound immune... 

Preferred Pl-based regimens are lopinavir/ritonavir plus lamivudine or emtricitabine plus another NRTI, usually zidovudine, stavudine or abacavir. Alternative combinations include other Pis with or without ritonavir, and two NRTIs. The combination of a protease inhibitor with ritonavir provides inhibition of cytochrome p450 enzymes and permits less frequent dosing of amprenavir, indinavir, lopinavir and saquinavir. Use of ritonavir in this setting is also known as boosting. ... 

As with other HIV-1 protease inhibitors, saquinavir may be associated with drug interactions as a result of the effect of saquinavir on the hepatic cytochrome P450 oxidase system. Although compared with other HIV protease inhibitors, saquinavir has less of an inhibitory effect on cytochrome P450 isozymes clinically relevant interactions can nevertheless occur. Drug interactions with saquinavir have been reviewed (3). 

Scheme 19.25 Molecular design strategies leading to a representative HIV-1 Protease Inhibitor drug, namely saquinavir 91. LE = Lead enhancement where synthesis of numerous analogs eventually led to the next depicted molecule. Note replacement of an Initial peptidic linkage with a hydroxyl-ethylene blolsoster. The latter has also become a key functional group In many of the other newer HIV-1 Protease inhibitors. (With permission from Proudfoot.)...

Virus replication in the presence of Saquinavir selects for drug-resistant virus. The primary saquinavir resistance mutation occurs at HIV protease codon 90 (a leucine-to-methionine substitution), although primary resistance also has been reported with a glycine-to-valine substitution at codon 48. Secondary resistance mutations occur at codons 36, 46, 82, 84, and others, and these are associated with clinical saquinavir resistance as well as cross-resistance to other HIV protease inhibitors. As is typical of HIV protease inhibitors, high-level resistance requires accumulation of multiple-resistance mutations. 

Of aU the HIV protease inhibitors, saquinavir is the least potent inhibitor of CYP3A4. Nonetheless, it is recommended that the drug not be coadministered with ergot derivatives, triazolam, midazolam, or other CYP3A4 substrates with a low therapeutic index. Saquinavir clearance is increased with CYP3A4 induction thus coadministration of rifampin, nevirapine, or efavirenz lowers saquinavir concentrations and should be avoided. The effect of nevirapine or efavirenz on saquinavir may be partially or completely reversed with ritonavir. 

In initial clinical trials, hard-gelatin capsules of saquinavir mesylate at the approved dose (600 mg three times daily) produced only modest virologic effect most likely because of poor oral bioavailability. Greater activity was achieved by increasing the dose fourfold, to 1200 mg six times daily. When combined with ritonavir and nucleoside analogs, saquinavir produces viral load reductions comparable with those of other HTV protease inhibitor regimens. 

Atazanavir is an antiretroviral agent approved for use in combination with other antiretroviral agents for the treatment of HIV infections. Atazanavir is a peptidomimetic transition-state inhibitor that targets HIV-1 protease and reduces the viral replication and, thus, the virulence of HIV-1. Similar to saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir, the drug is used in combination with RT inhibitors to produce excellent efficacy in patients with AIDS. 

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