Pharmacology Update
Lopinavir and Ritonavir Capsules and Oral Solution (Kaletra—Abbott)
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
A new combination protease inhibitor is the latest anti-HIV medication to be approved by the FDA. Abbott’s Kaletra combines lopinavir with a low dose of the previously approved ritonavir (Norvir). The combination takes advantage of ritonivir’s ability to inhibit the metabolism of lopinavir, increasing its plasma levels. Kaletra, which is to be used with other anti-HIV drugs, was given an accelerated approval by the FDA.
Indications
Lopinavir/ritonavir is indicated in combination with other antiretroviral drugs for the treatment of HIV infections in adults and pediatric patients as young as 6 months.1
Dosage
The recommended dose of lopinavir/ritonavir is 400 mg/100 mg (3 capsules or 5 mL) twice daily taken with food. A dose increase to 533 mg/133 mg (4 capsules or 6.5 mL) twice daily should be considered when used in combination with efavirenz or nevirapine in treatment of experienced patients where reduced susceptibility to lopinavir is suspected.1 The pediatric dose is 12 mg/kg twice daily in patients 7 kg up to 15 kg body weight, 10 mg/kg twice daily in those 15-40 kg, and an adult dose for those more than 40 kg.
To optimize bioavailability and reduce variability, lopinavir/ritonavir should be taken with food.
Kaletra is available as capsules containing 133.3 mg of lopinavir and 33.3 mg of ritonavir and 400 mg of lopinavir and 100 mg of ritonavir per 5 mL. The oral solution contains 42.4% of alcohol.
Potential Advantages
The combination has a low pill burden (3 capsules twice daily) that simplifies therapy and promotes adherence. Lopinavir/ritonavir is indicated for patients as young as 6 months of age—the broadest pediatric indication for a protease inhibitor.
Potential Disadvantages
Ritonavir is a potent inhibitor of cytochrome P450 CYP3A and, to a lesser degree, CYP2D6. Kaletra has the potential to inhibit the metabolism of numerous other drugs. Flecainide, propafenone, ergot derivatives, pimozide, midazolam, triazolam, rifampin, lovastatin, simvastatin, cisapride, astemizole, terfenadine, and St. Johns’ wort are either contraindicated or should not be co-administered with Kaletra.1
In addition, there are numerous other potential significant drug interactions that may require adjustment of doses and/or monitoring. For example, carbamazepine, phenytoin, phenobarbital, efavirenz, and nevirapine can induce the activity of CYP3A resulting in the reduction of lopinavir levels.
Significant dose reduction of rifabutin is recommended if it is co-administered with Kaletra. A complete list of potentially drug-drug interactions is provided in the product labeling.1
The most common side effects associated with lopinavir/ritonavir is diarrhea (14-24%) and nausea, which appears to occur more frequently in antiretroviral-naive patients (6-15%). Laboratory abnormalities include elevation of total cholesterol (6-27%) and triglycerides (5-26%). Higher incidences have been observed in antiretroviral-experienced patients.1 Pancreatitis, new onset diabetes, exacerbation of pre-existing diabetes, and hyperglycemia have been reported although causal relationships have not been established.1
Comments
Lopinavir/ritonavir is a novel combination that uses a metabolite enzyme inhibitor to enhance the plasma level of the active drug. When administered as the fixed combination, the plasma levels of lopinavir are 15-20-fold higher than those of ritonavir. The plasma levels of ritonavir are less than 7% of those achieved after a therapeutic dose of ritonavir and the in vitro antiviral activity is about 1/10th of that of lopinavir. The antiviral activity of Kaletra is solely attributed to lopinavir and apparently does not, at least in vitro, influence the selection of lopinavir-resistant virus.1 It is not clear how the low subtherapeutic doses of ritonavir will affect ritonavir resistance or other protease inhibitors that are cross resistant to ritonavir. The approval of lopinavir/ritonavir, like other anti-HIV agents, was based on improvement in HIV viral RNA levels and CD4 counts. In an ongoing trial (n = 653), lopinavir/ritonavir plus stavudine and lamivudine was compared to nelfinavir plus stavudine and lamuvidine in treatment-naive patients with mean baseline plasma HIV RNA of 4.9 log10 copies/mL.
Through 24 weeks, 79% of lopinavir/ritonavir patients had HIV RNA below 400 copies/mL compared to 70% for the nelfinavir combination. Discontinuation due to side effects were comparable, 2%.1 In patients who were one protease inhibitor experienced and nonnucleoside reverse transcriptase inhibitor-naive (n = 70), lopinavir/ritonavir and nevirapine and two NRTIs achieved HIV RNA levels less than 400 in 75% of patients after 72 weeks. These patients have mean baseline viral levels of 4.0 log10. Full details of these studies are not available as results have not been published.
Clinical Implications
Lopinavir/ritonavir provides an alternative to other protease inhibitors on the market. Its twice-daily dosing and low pill burden may favor medication adherence, but the drug combination is saddled with multiple drug-drug interactions since ritonavir is a potent inhibitor of CYP3A and to a lesser degree CYP 2D6. These cytochrome P450 enzymes are responsible for metabolizing a wide variety of drugs and endogenous chemicals.2,4 In addition, ritonavir is also an inducer of CYP1A4, glucuronosyl transferase, and possibly, CYP2C9 and CYP2C19.3 As a result, numerous drugs are contraindicated with lopinavir/ritonavir and many require dosage adjustments and/or monitoring. Abbott has agreed to develop educational material for patients and to provide information regarding drug interactions as part of its Phase IV commitments.5 Kaletra will be priced competitively to nelfinavir.
References
1. Kaletra Product Information. Abbott Laboratories. September 2000.
2. Slaughter R, Edwards DJ. Ann Pharmacother 1995; 29:619-624.
3. Hsu A, et al. Clin Pharmacokinet 1998;35:275-291.
4. Dresser GK, et al. Clin Pharmacokinet 2000;38:41-57.
5. FDC Report. The Pink Sheet 2000;62(39):12-13.
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