Ritonavir with other 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... 

In a prospective, non-randomized analysis of 212 patients treated with a regimen containing a protease inhibitor, the overall incidences of hypertriglyceridemia and hypercholesterolemia at 12 months of treatment were 38% and 25% respectively (155). Increased concentrations of triglycerides and LDL cholesterol were more pronounced in patients taking ritonavir or lopinavir/rito-navir compared with other protease inhibitors. 

The manufacturers of pethidine oral preparations and injection contraindicate or advise against its use with ritonavir because of the risk of norpethidine toxicity. Long-term use of pethidine with other protease inhibitors e.g. tipranavir, which are given with low-dose ritonavir is also not recommended. ... 

Ritonavir markedly increases the levels of fentanyl, and markedly increases alfentanil-induced miosis. Other protease inhibitors such as nelfinavir may have a similar effect Care should also be taken if ritonavir is used with other protease inhibitors as a pharmacokinetic enhancer. 

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-... 

Although information is limited, these pharmacokinetic interactions are predictable, and potentially serious. To date, clinically relevant increases in calcium-channel blocker levels or effects have been shown for nelfinavir with nifedipine or felodipine, indinavir/ritonavir with amlodipine, diltiazem or nifedipine, and atazanavir with diltiazem. Caution would be required with any of these combinations, anticipating the need to use lower doses of the calcium-channel blocker. The manufacturers specifically recommend that if diltiazem is given with atazanavir the initial dose of diltiazem should be reduced by 50% with subsequent dose titration and ECG monitoring. They also note that verapamil levels may be raised and therefore advise caution. Similarly, the manufaeturers of nifedipine say that blood pressure monitoring is required and a reduction in nifedipine dose may be neeessary if it is given with HIV-protease inhibitors. However, some UK manufacturers (e.g. felodipine, lercanidipine, nimodipine ) recommend avoiding the concurrent use of ritonavir and other protease inhibitors if possible. 

A 51-year-old woman was admitted to hospital with a 4-day history of muscular aches and weakness. Among other drugs, she had been taking zidovudine, lamivudine, indinavir, and simvastatin for 2 years. Ritonavir 100 mg twice daily had been added to her usual regimen 2 weeks previously. The rhabdomyolysis was therefore attributed to an interaction between ritonavir and simvastatin. Another similar case has also been reported. See also (b) above and (e) below for interactions of ritonavir combined with other protease inhibitors. 

The protease inhibitors are used in the multidrug therapy of HIV infection. Resistance to the HIV protease inhibitors results from mutations in the protease gene and perhaps the cleavage sites of gag-pol. Although different protease mutations tend to be associated with resistance to individual drugs, resistance to one protease inhibitor is often associated with a less than optimal response to other agents of this class. Indinavir, ritonavir, and lopinavir require more mutations to lose their effectiveness than do the other protease inhibitors. 

Although ritonavir (Norvir) is a potent inhibitor of HIV-1 and HIV-2 protease, 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... 

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. 

Resistance may be associated with multiple mutations, and the number of codon alterations (typically substitutions) present tends to predict the level of phenotypic resistance. Mutations at positions at 46 or 82 seem to predict phenotypic resistance most consistently. Resistance to indinavir is associated with a loss of susceptibility to ritonavir however, susceptibility to other protease inhibitors in indinavir-resistant isolates is less predictable. 

An important consideration in the use of all HIV-1 protease inhibitors, but of ritonavir in particular, is their potential for drug interactions through their effects on cytochrome P450 isozymes. The various interactions of ritonavir with other antiretroviral drugs have been reviewed (139). Ritonavir, which inhibits CYP2D6, the principal pathway by which MDMA is metabolized, can also produce clinically relevant interactions with recreational drugs (140). 

By inhibiting their metabolism, ritonavir potentiates the actions of other protease inhibitors. The addition of delavirdine instead of another NNRTI in three patients taking protease inhibitors plus ritonavir further increased the exposure to the protease inhibitors (6). Combining delavirdine with indinavir removes the food restrictions during indinavir administration (4). The superior virological response observed in antiretroviral regimens containing delavirdine and protease inhibitors has been attributed in part to the pharmacokinetic interaction. 

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). 

Other protease inhibitors have also been rarely associated with kidney injury. A single case of interstitial nephritis and reversible AKI in a patient treated with atazanavir has also been reported [153] Acute kidney injury attributed to ritonavir has been reported in several patients [154-157], the majority of whom were receiving concomitant nephrotoxic medications, while others had preexisting kidney disease or were volume depleted. In several patients, AKI recurred upon ritonavir rechallenge. Kidney biopsies were not performed, so histopathologic correlates and etiology of kidney injury were not precisely defined. 

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). 

Figure 19.30 Ritonavir 92 bound to HIV Protease with resistance mutation sites aiso noted. The orange spheres represent the aipha-carbons of Vai 82 and the biue spheres represent additionai mutations in the protease enzyme that confer resistance to other protease inhibitors. The CYP450 issue was iocaiized to the ieft-hand side thiazoie ring. Modification of this ring system to the dimethyiphenyi ether gave iopinavir. (With permission from Proudfoot.)...

Ritonavir is a protease inhibitor that inhibits human immunodeficiency virus (HIV) protease, the enzyme required to form functional proteins in HIV-infected cells. It is indicated in the treatment of HIV infections in combination with other antiretroviral agents. 

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. 

Case reports surest that ritonavir markedly increases carbamazepine levels and toxicity. Cases have also been reported with lopinavir/ritonavir and nelfinavir. Carbamazepine reduces indinavir levels and efficacy, and would also be expected to decrease levels of other protease inhibitors. 

Ritonavir impairs the clearance of trazodone with an increased potential for adverse effects. Other protease inhibitors may interact similarly. 

In a nested case-control study conducted by the Swiss HIV Cohort there was a strong association between prolonged exposure to didanosine and non-cirrhotic portal hypertension [107 ]. In 15 patients with non-cirrhotic portal hypertension and 75 controls matched for duration of HIV infection, absence of viral hepatitis, and duration of follow-up, cumulative exposure to antiretroviral drug therapy (OR per year = 1.3 95% Cl = 1.0,1.6), nucleoside reverse transcriptase inhibitors (OR = 1.3 95% Cl = 1.1, 1.7), didanosine (OR = 3.4 95% Cl = 1.5, 8.1), ritonavir (OR = 1.4 95% Cl = 1.0, 1.9), and nelfinavir (OR = 1.4 95% Cl = 1.0,1.9) were longer in the patients with portal hypertension. Exposure to non-nucleoside reverse transcriptase inhibitors and other protease inhibitors were not different. 

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