Lopimune Tablets ( Ritonavir 50mg,Lopinavir 200mg)

Lopinavir is an HIV-1 protease inhibitor used in combination with ritonavir to treat human immunodeficiency virus (HIV) infection.

Lopinavir is an antiretroviral protease inhibitor used in combination with other antiretrovirals in the treatment of HIV-1 infection. Lopinavir is marketed and administered exclusively in combination with ritonavir - this combination, first marketed by Abbott under the brand name Kaletra in 2000, is necessary due to lopinavir's poor oral bioavailability and extensive biotransformation. Ritonavir is a potent inhibitor of the enzymes responsible for lopinavir metabolism, and its co-administration "boosts" lopinavir exposure and improves antiviral activity. Like many other protease inhibitors (e.g. saquinavir, nelfinavir), lopinavir is a peptidomimetic molecule - it contains a hydroxy ethylene scaffold that mimics the peptide linkage typically targeted by the HIV-1 protease enzyme but which itself cannot be cleaved, thus preventing the activity of the HIV-1 protease.

Lopinavir is currently under investigation in combination with ritonavir for the treatment of COVID-19 caused by SARS-CoV

Structure

Indication

The combination product lopinavir/ritonavir, marketed under the brand name Kaletra, is indicated in combination with other antiretrovirals for the treatment of HIV-1 infection in adults and pediatric patients ≥14 days old.

Pharmacodynamics

Lopinavir inhibits the activity of an enzyme critical for the HIV viral lifecycle. It has a moderate duration of action necessitating once or twice daily dosing. Lopinavir, like other protease inhibitors, has a propensity for participating in drug interactions - use caution when administering lopinavir to patients maintained on other pharmaceutical agents as pharmacodynamic and pharmacokinetic interactions are common. Fatal hepatotoxicity and pancreatitis have been noted in patients undergoing therapy with lopinavir and patients with an increased baseline risk of these events should be monitored closely throughout therapy.

Mechanism of action

The HIV lifecycle is comprised of 3 distinct stages: assembly, involving the creation and packaging of essential viral components; budding, wherein the viral particle crosses the host cell plasma membrane and forms a lipid envelope; and maturation, wherein the viral particle alters its structure and becomes infectious. At the center of this lifecycle is the Gag polyprotein which, along with the products of its proteolysis, coordinate these stages and function as the major structural proteins of the virus. The HIV-1 protease enzyme, a dimeric aspartic protease, is the enzyme responsible for cleaving the Gag polyprotein and thus plays a critical role in many aspects of the HIV viral lifecycle.2

Lopinavir is an inhibitor of the HIV-1 protease enzyme. Its design is based on the "peptidomimetic" principle, wherein the molecule contains a hydroxy ethylene scaffold that mimics the normal peptide linkage (cleaved by HIV protease) but which itself cannot be cleaved.5 By preventing HIV-1 protease activity, and thus the proteolysis of the Gag polyprotein, lopinavir results in the production of immature, non-infectious viral particles.

Absorption

When administered alone, lopinavir has exceptionally low oral bioavailability (~25%) - for this reason, it is exclusively co-administered with ritonavir, which dramatically improves bioavailability, hinders drug metabolism, and allows for the attainment of therapeutic lopinavir concentrations.3,4 Following oral administration of lopinavir/ritonavir, maximal plasma concentrations are achieved at approximately 4.4 hours (Tmax), and the Cmax and AUCtau are 9.8 ± 3.7 - 11.8 ± 3.7 µg/mL and 92.6 ± 36.7 - 154.1 ± 61.4 μg•h/mL, respectively.

Relative to administration in the fasted state, administration with a meal increases the AUC of the tablet formulation slightly (~19%) but dramatically increases the AUC of the oral solution formulation (~130%).

Volume of distribution

The volume of distribution of lopinavir following oral administration is approximately

Protein binding

Lopinavir is >98% protein-bound in plasma. It binds to both alpha-1-acid glycoprotein and albumin but exhibits a greater affinity for alpha-1-acid glycoprotein.

Metabolism

Lopinavir undergoes extensive oxidative metabolism, almost exclusively via hepatic CYP3A isozymes.10 Co-administration with ritonavir, a potent inhibitor of CYP3A enzymes, helps to stave off lopinavir's biotransformation and increase plasma levels of active antiviral drug. Twelve metabolites have been identified in vitro, with the C-4 oxidation products M1, M3, and M4 being the predominant metabolites found in plasma. The structures of these primary metabolites have been identified, but precise structural information regarding the remaining minor metabolites has not been elucidated.

Route of elimination

Lopinavir is primarily eliminated in the feces. Following oral administration, approximately 10.4 ± 2.3% of the administered dose is excreted in the urine and 82.6 ± 2.5% is excreted in the feces. Unchanged parent drugs accounted for 2.2% and 19.8% of the administered dose in urine and feces, respectively.

Half-life

The elimination half-life of lopinavir is 6.9 ± 2.2 hours.

Clearance

The estimated apparent clearance following oral administration is approximately

Toxicity

As lopinavir is only available in combination with ritonavir, experience with acute lopinavir overdose in isolation is limited. The risk related to overdose appears more pronounced in pediatric patients. One case report detailed a fatal cardiogenic shock in a 2.1kg infant following an approximately 10-fold overdose of Kaletra oral solution, while other reported reactions to overdose in infants include complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure. The oral Kaletra solution is highly concentrated, posing a greater risk of overdose, and contains approximately 42% (v/v) ethanol, further increasing risk in children and infants.7

There is no antidote for lopinavir overdose. Treatment of overdose should consist largely of supportive measures and close observation of vital signs and clinical status of the affected patient. Consideration should be given to the removal of unabsorbed drug-using gastric lavage or activated charcoal if clinically indicated. Dialysis is unlikely to be of benefit as lopinavir is highly protein-bound but may help to remove ethanol and propylene glycol from the circulation in the case of overdose with Kaletra oral solution.7