Lopinavir with other protease inhibitors

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 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. 

Lopinavir is a protease inhibitor combination. Lopinavir inhibits HIV protease, the enzyme required to form functional proteins in HIV-infected patients. Ritonavir inhibits the cytochrome P450 (CYP) 3A-mediated metabolism of lopinavir, increasing lopinavir plasma concentrations. They are indicated in the treatment of HIV infections in combination with other antiviral agents. 

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. ... 

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. 

A number of other protease inhibitors (Fig. 23.16) have been developed in the last few years with the aim of improving pharmacokinetic profile. One of the first of these was amprenavir, which does not contain peptide bonds which slows down its clearance from the body. Its pharmokinetics are further improved when it is administered as its phosphate prodmg fosamprenavir. Lopinavir was also developed to give improved pharmacokinetics. Its effectiveness is improved by co-administration with... 

Interactions. Involvement of protease inhibitors with the cytochrome P450 system provides scope for interaction with numerous substances. Agents that induce P450 enzymes (e.g. rifampicin, St John s wort) accelerate their metabolism, and reduce plasma concentration enzyme inhibitors (e.g. ketoconazole, cimetidine) raise their plasma concentration competition with other drugs for the cytochrome enzymes can lead to variable results. Ritonavir is itself a powerful inhibitor of CYP 3A4 and CYP 2D6. This effect is utilised when ritonavir in small quantity is combined (in capsules) with lopinavir to inhibit its metabolism and increase its therapeutic efficacy. The present account should be sufficient to warn the physician, and thereby the patient, to take particular heed when seeking to co-administer any drug a with protease inhibitor. 

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. ... 

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. 

The manufacturer of ritonavir predicts that it will decrease the plasma levels of atovaquone, - by inducing atovaquone glucuronidation. They say that the clinical significance of this prediction is unknown, but that an increase in the atovaquone dose might be needed. Careful monitoring of serum levels and/or therapeutic effects is recommended when atovaquone is given with ritonavir as a pharmacokinetic enhancer or as an antiretroviral. This predicted interaction would therefore apply to lopinavir/ritonavir and any other boosted protease inhibitors. However, there does not appear to be any actual data to prove that the interaction occurs or is clinically relevant. 

Various dual combinations of proteas e inhibitors have been tried, or are us ed, to boos t the levels and cons equently the efficacy of one of the proteas e inhibitors . Ritonavir is the mos t potent at boos ting levels of the other proteas e inhibitors , and current guidelines recommend the us e of low-dos e ritonavir in combination with atazanavir, darunavir, fos amprenavir, lopinavir, s aquina-vir, or tipranavir. Some proteas e inhibitor combinations may re-s ult in additive toxicity (indinavir and ritonavir or atazanavir). Although this monograph s ummaris es the pharmacokinetic interactions and dos ing recommendations current guidelines should be consulted when choosing protease inhibitor combinations. 

The initial search for an inhibitor of the SARS 3CL protease focused on preexisting drugs and compounds, some tested empirically and others selected based on modeling. The HlV-1 PI nelfinavir and lopinavir/ritonavir have been considered, with the latter actually used clinically in SARS CoV-infected subjects. The rhi-novirus inhibitor ruprintrivir and related compounds have also been tested (reviewed in Fear et al. 2007). However, in the absence of any elements of specificity, these preexisting compounds would be expected to have low potency. 

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