Usage
Lopinavir + Ritonavir is an antiretroviral medication specifically classified as a protease inhibitor. It is primarily prescribed for the treatment of HIV-1 infection, in combination with other antiretroviral agents. It works by inhibiting the activity of HIV protease, an enzyme crucial for the replication of the virus. This inhibition prevents the virus from assembling new infectious particles. While Lopinavir/Ritonavir showed promise in some laboratory studies against SARS-CoV-2, clinical trials have demonstrated it is not effective for treating COVID-19.
Alternate Names
The combination is often referred to as LPV/r. A widely recognized brand name for Lopinavir + Ritonavir is Kaletra.
How It Works
Pharmacodynamics: Lopinavir + Ritonavir primarily targets HIV-1 protease, thereby disrupting the final stage of viral replication. Ritonavir, while also a protease inhibitor, serves primarily to boost Lopinavir levels by inhibiting CYP3A4, the enzyme responsible for Lopinavir metabolism. This “boosting” effect allows for lower doses of Lopinavir and simplifies the dosing regimen.
Pharmacokinetics: Lopinavir and Ritonavir are both orally administered and absorbed in the gastrointestinal tract, ideally with food to enhance absorption. Ritonavir’s inhibition of CYP3A4 significantly increases the bioavailability of Lopinavir. Both drugs are primarily metabolized in the liver by CYP3A4 (though Ritonavir’s effects are most relevant) and are primarily excreted in the feces, with negligible renal excretion. Lopinavir exhibits high plasma protein binding.
Mode of Action: The primary mechanism of action involves competitive binding to the active site of HIV-1 protease. This binding prevents the enzyme from cleaving viral polyproteins into functional components, essential for the production of mature, infectious viral particles. The result is the production of immature, non-infectious virions.
Elimination Pathways: Primarily hepatic metabolism via CYP3A4, followed by fecal excretion. Renal elimination is negligible.
Dosage
Standard Dosage
Adults: 400 mg lopinavir/100 mg ritonavir twice daily, or 800 mg lopinavir/200 mg ritonavir once daily (only recommended for protease inhibitor-naïve patients). Administer with food.
Children (over 6 months): Dosing is weight-based and must be determined by a physician:
- Tablets: For children who can swallow tablets whole, weight-based dosing is used.
- Oral Solution: For infants and younger children, an oral solution is available and dosing is calculated based on body weight or body surface area.
Special Cases:
- Elderly Patients: No specific dose adjustments are recommended, but close monitoring is advised due to potential age-related changes in hepatic function.
- Patients with Renal Impairment: No dose adjustment is required.
- Patients with Hepatic Dysfunction: Contraindicated in patients with severe hepatic impairment. Caution is advised in patients with mild to moderate impairment, with potential for dose reduction considered.
- Patients with Comorbid Conditions: Close monitoring and potential dose adjustments may be required for patients with conditions such as hyperlipidemia, diabetes, or cardiovascular disease.
Clinical Use Cases
Lopinavir + Ritonavir is not indicated for use in clinical situations like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency scenarios outside of its established role in managing HIV infection.
Dosage Adjustments
Dose adjustments are necessary when co-administered with certain medications like nevirapine, efavirenz, or nelfinavir due to drug interactions involving CYP3A4. Dosage should be increased in pregnant women during the second and third trimesters, typically to lopinavir 600 mg/ritonavir 150 mg twice daily.
Side Effects
Common Side Effects:
Diarrhea, nausea, vomiting, hypertriglyceridemia, hypercholesterolemia, headache, asthenia, abdominal pain.
Rare but Serious Side Effects:
Pancreatitis, hepatotoxicity, severe skin reactions (e.g., Stevens-Johnson syndrome), cardiac arrhythmias (including QT prolongation), new onset diabetes or worsening of existing diabetes.
Long-Term Effects:
Hyperlipidemia, lipodystrophy, insulin resistance, increased risk of cardiovascular disease.
Adverse Drug Reactions (ADR):
Hepatotoxicity, pancreatitis, severe skin reactions, rhabdomyolysis.
Contraindications
Hypersensitivity to lopinavir, ritonavir, or any component of the formulation. Severe hepatic impairment. Co-administration with drugs highly dependent on CYP3A for clearance and those where elevated plasma concentrations are associated with serious or life-threatening reactions (e.g., alfuzosin, amiodarone, rifampin, pimozide, astemizole, terfenadine, ergot derivatives, midazolam, triazolam). Drugs that are potent CYP3A inducers are contraindicated (e.g., rifampicin, St. John’s Wort), as they decrease lopinavir concentrations.
Drug Interactions
Lopinavir + Ritonavir is a potent inhibitor of CYP3A4 and can significantly affect the metabolism of numerous drugs, including but not limited to: HMG-CoA reductase inhibitors (statins), some antiarrhythmics, some anticonvulsants, some benzodiazepines, some immunosuppressants. Concomitant use of these medications requires careful monitoring and potential dose adjustment. Conversely, CYP3A4 inducers can decrease lopinavir concentrations, which can lead to treatment failure. Interactions with certain drugs, such as sildenafil (for pulmonary arterial hypertension), are contraindicated. Alcohol, grapefruit juice, and smoking can also interact with this medication.
Pregnancy and Breastfeeding
Limited data suggests Lopinavir + Ritonavir is not a major teratogen. However, decreased Lopinavir exposure during pregnancy may require dose adjustments, especially in the second and third trimesters. Ritonavir is present in breast milk, though at low levels. While no adverse effects have been reported in breastfed infants, the recommendation is to avoid breastfeeding if possible or closely monitor the infant for side effects.
Drug Profile Summary
- Mechanism of Action: HIV-1 protease inhibitor.
- Side Effects: Diarrhea, nausea, vomiting, hyperlipidemia, hypercholesterolemia, pancreatitis, hepatotoxicity.
- Contraindications: Severe hepatic impairment, concomitant use of potent CYP3A4 inducers or substrates with narrow therapeutic indices.
- Drug Interactions: Numerous drug interactions primarily through CYP3A4 inhibition.
- Pregnancy & Breastfeeding: Use with caution and dose adjustment during pregnancy; breastfeeding not recommended if possible.
- Dosage: Adult: 400/100 mg twice daily or 800/200 mg once daily (protease inhibitor-naive patients); Pediatric: weight-based dosing.
- Monitoring Parameters: HIV viral load, CD4 count, lipid profile, liver function tests, blood glucose, electrocardiogram (ECG) for QT prolongation.
Popular Combinations
Lopinavir + Ritonavir is often used in combination with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) as part of combination antiretroviral therapy (cART).
Precautions
- General Precautions: Monitor for hepatotoxicity, pancreatitis, hyperlipidemia, and cardiac arrhythmias.
- Specific Populations: Close monitoring and dose adjustments as needed for pregnant women, patients with hepatic dysfunction, and those taking interacting medications.
- Lifestyle Considerations: Advise patients on potential interactions with alcohol, grapefruit juice, and smoking.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Lopinavir + Ritonavir?
A: Adults: 400 mg/100 mg twice daily or 800 mg/200 mg once daily (for treatment-naive individuals). Pediatric dosing is weight-based and requires careful calculation by a clinician.
Q2: What are the most common side effects?
A: Diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia.
Q3: What are the contraindications for using Lopinavir + Ritonavir?
A: Severe hepatic impairment, concomitant use with certain medications metabolized by or affecting CYP3A4, particularly potent CYP3A inducers.
Q4: Can Lopinavir + Ritonavir be used during pregnancy?
A: Yes, but with caution and appropriate dose adjustments, particularly during the second and third trimesters. Once-daily dosing is not recommended. Avoid the oral solution during pregnancy due to ethanol and propylene glycol content.
Q5: Is Lopinavir + Ritonavir safe for breastfeeding mothers?
A: While Ritonavir is present in breastmilk, it’s generally recommended that women with HIV infection do not breastfeed due to the risk of HIV transmission. Discuss the risk/benefit assessment with the patient. If choosing to breastfeed, closely monitor the infant.
Q6: What are the key drug interactions to be aware of?
A: Lopinavir + Ritonavir interacts with numerous drugs metabolized by CYP3A4. Co-administration with certain medications requires dose adjustments or is contraindicated. Refer to the drug interaction resources for a comprehensive list.
A: Primarily hepatic metabolism via CYP3A4.
Q8: What monitoring is recommended for patients on Lopinavir + Ritonavir?
A: HIV viral load, CD4 count, lipid profile, liver function tests, blood glucose, and ECG monitoring for QT prolongation.
Q9: What is the role of Ritonavir in this combination?
A: Ritonavir primarily acts as a pharmacokinetic enhancer, inhibiting the metabolism of Lopinavir and allowing for reduced Lopinavir doses and simplified dosing schedules.
Q10: Is Lopinavir/Ritonavir effective in treating COVID-19?
A: No. Clinical trials have demonstrated that Lopinavir/Ritonavir is not an effective treatment for COVID-19.
