Indinavir with other protease inhibitors

The answer is d. (Kalzung, p 839.) Indinavir is a specific inhibitor of IIIV-1 proteases. Cross-resistance can occur with other protease inhibitors. 

The results of a questionnaire survey of 878 people with HIV infection treated with antiretroviral drugs confirmed the risk of arthralgias in patients taking indinavir. The authors suggested that crystal deposition in joints, analogous to the crystalluria with nephrolithiasis that indinavir and other protease inhibitors can cause, might be responsible. 

Florence E, Schrooten W, Verdonck K, Dreezen C, Colebunders R. Rheumatological comphcations associated with the use of indinavir and other protease inhibitors. Ann Rheum Dis 2002 61(l) 82-4. 

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). 

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. 

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-... 

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. 

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. 

Pharmacokinetics and clinical use Oral bioavailability is good except in the presence of food. Clearance is mainly via the liver, with about 10% renal excretion. Like the other protease inhibitors, indinavir is used in dmg combinations, most often with two 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. 

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. 

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... 

If St. John s wort can alter levels of cyclosporin in the blood, might it not also interfere with the action of other medications Recent research indicates that it can. Not surprisingly, the affected drugs are those that, like cyclosporin, are also metabolized by cytochrome enzymes. Protease inhibitors, used in the treatment of hiv infections, are a prime example. Because of the popularity of St. John s wort as an antidepressant and the incidence of depression in patients diagnosed with HIV infections, researchers at the U.S. National Institutes of Health decided to investigate the consequences of using the herbal remedy and the protease inhibitor indinavir concurrently. Doctors prescribe indinavir to prevent the hiv virus... 

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. ... 

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