Patented in 1995 and approved for medical use in 2000,[2] lopinavir—co-administered with ritonavir—is now considered a second-line therapy in high-income countries but remains widely prescribed in low- and middle-income countries (LMICs), particularly for children living with HIV. The medication is available as both a tablet and an oral solution, the latter being a preferred option for pediatric use. During the early stages of the COVID-19 pandemic, lopinavir was repurposed in an attempt to inhibit the protease activity of the SARS-CoV-2 virus.
BRAND NAMES
Kaletra is the original and most widely recognized brand name for the combination drug containing lopinavir and ritonavir.
MECHANISM OF ACTION
Lopinavir works by inhibiting the HIV-1 protease enzyme. It was designed using the "peptidomimetic" approach, meaning it features a hydroxyethylene scaffold that imitates the natural peptide bond typically cleaved by HIV protease—but cannot be cleaved itself. By blocking the activity of HIV-1 protease and preventing the cleavage of the Gag polyprotein, lopinavir leads to the formation of immature, non-infectious virus particles.
PHARMACOKINETICS
Absorbtion:
After absorption, lopinavir is extensively metabolized in the liver by the enzyme CYP3A4. However, when combined with ritonavir—an inhibitor of CYP3A4—its metabolism is slowed, resulting in higher systemic levels of lopinavir.
Distribution:
lopinavir has a volume of distribution of approximately 16.9 liters. In plasma, more than 98% of lopinavir is bound to proteins, primarily alpha-1-acid glycoprotein and albumin, with a stronger binding affinity for alpha-1-acid glycoprotein.
Metabolism:
Lopinavir undergoes rapid and extensive metabolism, primarily by the cytochrome P450 (CYP) enzyme system, specifically the CYP3A4 isoenzyme. This rapid metabolism is why lopinavir is co-administered with a low dose of ritonavir, another protease inhibitor.
Excretion:
Lopinavir is mainly eliminated through the feces after being extensively metabolized in the liver by the CYP3A4 enzyme. Following oral administration, it undergoes significant first-pass metabolism, with less than 3% of the unchanged drug excreted in urine and approximately 20% appearing in feces.
PHARMACODYNAMICS
Lopinavir works by inhibiting a key enzyme essential to the HIV replication cycle. It has a moderate duration of action, requiring dosing once or twice daily. Like other protease inhibitors, lopinavir is prone to drug interactions, so caution is advised when used alongside other medications, as both pharmacokinetic and pharmacodynamic interactions are common. Cases of fatal hepatotoxicity and pancreatitis have been reported during lopinavir therapy; therefore, patients with a higher baseline risk for these conditions should be closely monitored throughout treatment.
ADMINISTRATION
Lopinavir is administered orally, typically in combination with ritonavir, with specific instructions depending on the formulation (tablets, oral solution, or pellets). It is essential to follow the guidance of a healthcare provider for the correct dosage and administration method.
DOSAGE AND STRENGTHS
Lopinavir is most commonly administered as a fixed-dose combination with ritonavir, marketed under the brand name Kaletra. Ritonavir acts as a pharmacokinetic enhancer by inhibiting the CYP3A4 enzyme, thereby increasing the plasma concentration of lopinavir. The combination is available in oral tablet form, with each film-coated tablet containing lopinavir 200 mg and ritonavir 50 mg. For adults and adolescents, the standard recommended dose is 400 mg/100 mg (two tablets) twice daily. Alternatively, 800 mg/200 mg (four tablets) once daily may be used in select patients who have no lopinavir-associated resistance mutations and are not pregnant.
DRUG INTERACTIONS
Lopinavir is exclusively administered in combination with ritonavir, as ritonavir dramatically increases the concentration of lopinavir in the blood. The vast potential for drug-drug interactions (DDIs) is mainly driven by ritonavir, which is a potent inhibitor of the CYP3A4 enzyme and affects other enzymes and transporter proteins. These interactions can cause the plasma concentration of other drugs to increase, leading to toxic effects, or to decrease, which can reduce their therapeutic effectiveness
FOOD INTERACTIONS
Avoid using St. John's Wort while taking this medication, as it induces CYP3A enzymes, which can lower drug plasma levels and lead to treatment failure. The oral solution should be taken with food to enhance absorption, whereas the tablet form can be taken with or without food.
CONTRAINDICATIONS
Lopinavir and ritonavir are contraindicated in patients who have previously experienced clinically significant hypersensitivity reactions—such as toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, or angioedema—to any of the components, including ritonavir.
SIDE EFFECTS
Pain or tenderness in the upper abdomen
Pale-colored stools
Dark urine
Loss of appetite
Nausea
Unusual tiredness or weakness
Yellowing of the eyes or skin
OVER DOSE
Overdose may cause gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain.
There is no specific antidote for lopinavir overdose; treatment is generally supportive and symptomatic.
Patients should be closely monitored for any signs of toxicity, including liver function abnormalities or cardiac effects.
TOXICITY
Lopinavir toxicity can cause common side effects including diarrhea, headache, nausea, vomiting, rash, and insulin resistance. In rare cases, more severe effects have been observed, such as pericardial edema, tail shortening in aquatic organisms, inflammation, and oxidative stress resulting from environmental exposure.
