Lopinavir

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Listed in ZINC15

Colorless solid from ethyl acetone

White to light tan powder

Practically insoluble

Practically insoluble in water

Freely soluble in methanol and ethanol; soluble in isopropanol

1.92e-03 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Protease Inhibitors

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Based on the provided data, 18 months shelf life has been granted for the soft capsules when stored within their container at 5 °C with the option for room temperature storage after dispensing to the patients for up to 42 days. ... Based on the preliminary data, 18 months shelf life is acceptable when the oral solution is stored within its container at 5 °C, with the option for room temperature storage after dispensing to the patients for up to 42 days.

Stable if stored as directed; avoid strong oxidizing agents

This chemical does not meet GHS hazard criteria for 1.6% (1 of 61) of reports.

Warning

H315 (88.5%): Causes skin irritation [Warning Skin corrosion/irritation]

P260, P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 61 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lopinavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Unusual fire hazard: emits toxic fumes such as carbon monoxide, etc.

Emits /nitrogen oxides/ .. under fire conditions.

Extinguisher Media: Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... Firefighting Procedures: As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Accidental release measures: After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely- powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material /in accordance with prevailing country, federal, state and local regulations/.

Spill Response: Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Handling should only be performed by personnel trained and familiar with handling of potent active pharmaceutical ingredients.

Respiratory Protection: Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used. Gloves: Chemically compatible Eye Protection: Safety glasses or goggles Protective Clothing: Protect exposed skin.

Engineering controls such as exhaust ventilation are recommended.

Possible pharmacokinetic interaction with amiodarone, bepridil (no longer commercially available in the US), lidocaine (systemic), and quinidine (increased plasma concentrations of the antiarrhythmic agent). Use with caution. Monitor plasma concentrations of the antiarrhythmic agents if used concomitantly with lopinavir/ritonavir.

Pharmacokinetic interaction (increased alfuzosin plasma concentrations) may result in hypotension. Concomitant use of lopinavir/ritonavir and alfuzosin is contraindicated.

Lopinavir/ritonavir induces glucuronidation (i.e., increases biotransformation of some drugs metabolized by glucuronidation).

The fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) inhibits the cytochrome P-450 (CYP) isoenzyme; potential pharmacokinetic interactions with drugs metabolized by CYP3A (altered metabolism of the drug metabolized by CYP3A). Concomitant use with some drugs that are CYP3A substrates is contraindicated; concomitant use with other drugs that are CYP3A substrates may require dosage adjustment or additional monitoring. Lopinavir and ritonavir are metabolized by CYP3A; potential pharmacokinetic interactions with drugs that inhibit or induce CYP3A (altered metabolism of lopinavir).

For more Interactions (Complete) data for Lopinavir (61 total), please visit the HSDB record page.

Some degree of serum aminotransferase elevations occur in a high proportion of patients taking lopinavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (>5 times the upper limit of normal) are found in 3% to 10% of patients, although rates may be higher in patients with HIV-HCV coinfection. These elevations are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent liver disease due to lopinavir/ritonavir occurs, but is rare. The latency to onset of symptoms or jaundice is usually 1 to 8 weeks and the pattern of serum enzyme elevations varies from hepatocellular to cholestatic or mixed. The injury is usually self-limited; however, fatal cases have been reported. In addition, initiation of lopinavir/ritonavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy, and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Lopinavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including lopinavir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

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.

The HIV lifecycle is comprised of 3 distinct stages: assembly, involving 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. Lopinavir is an inhibitor of the HIV-1 protease enzyme. Its design is based on the "peptidomimetic" principle, wherein the molecule contains a hydroxyethylene scaffold which mimics the normal peptide linkage (cleaved by HIV protease) but which itself cannot be cleaved. 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.

/The researchers/ have previously shown that the HIV protease inhibitor lopinavir has selective toxicity against human papillomavirus (HPV)-positive cervical carcinoma cells via an unknown mechanism. SiHa cervical carcinoma cells were stably transfected with the proteasome sensor vector pZsProSensor-1 to confirm lopinavir inhibits the proteasome in these cells. The Panorama Xpress profiler 725 antibody array was then used to analyse specific changes in protein expression in lopinavir-treated versus control untreated SiHa cells followed by PCR and western blotting. Colorimetric growth assays of lopinavir-treated E6/E7 immortalised versus control human keratinocytes were performed. Targeted small interfering RNA gene silencing followed by growth assay comparison of lopinavir-treated/untreated SiHa cells was also used. Lopinavir induced an increase in the fluorescence of pZsProSensor-1 transfected SiHa cells, indicative of proteasomal inhibition. Ribonuclease L (RNASEL) protein was shown to be up-regulated in lopinavir-treated SiHa cells, which was confirmed by PCR and western blot. Targeted silencing of RNASEL reduced the sensitivity of SiHa cells to lopinavir. Selective toxicity against E6/E7 immortalised keratinocytes versus control cells was also seen with lopinavir and was associated with up-regulated RNASEL expression. These data are consistent with the toxicity of lopinavir against HPV-positive cervical carcinoma cells being related to its ability to block viral proteasome activation and induce an up-regulation of the antiviral protein RNASEL. This is supported by the drug's selective toxicity and up-regulation of RNASEL in E6/E7 immortalised keratinocytes combined with the increased resistance to lopinavir observed in SiHa cells following silencing of RNASEL gene expression.

Lopinavir inhibits replication of HIV type 1 (HIV-1) by interfering with HIV protease. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes to form structural proteins of the virion core and essential viral enzymes. By interfering with the formation of these essential proteins and enzymes, lopinavir blocks maturation of the virus and causes formation of nonfunctional, immature, noninfectious virions. Lopinavir also has some in vitro activity against HIV type 2 (HIV-2).

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

After single dose administration, mean elimination half-life ranged between 2 to 3 hours and seemed to be increased after multiple dose administration (about 4-6 hr).

Lopinavir undergoes extensive oxidative metabolism, almost exclusively via hepatic CYP3A isozymes. 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.

Lopinavir was metabolised in rat, dog and human primarily by hepatic CYP3A4 isoenzymes. Radioactivity in rat and dog faeces consisted largely of unchanged parent compound after oral administration. Although there were similarities in metabolite pattern between rat, dog and human, qualitative and quantitative differences were observed. The metabolism of lopinavir was sensitive to inhibition of ritonavir, which is in accordance with the inhibition of metabolic clearance of lopinavir by ritonavir observed in the rat.

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A (14)C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.

2494G1JF75

LOPINAVIR

Mechanisms of Action [MoA] - HIV Protease Inhibitors

Established Pharmacologic Class [EPC] - Protease Inhibitor

Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors

Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP3A.

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. 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%).

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 drug accounted for 2.2% and 19.8% of the administered dose in urine and feces, respectively.

The volume of distribution of lopinavir following oral administration is approximately 16.9 L.

The estimated apparent clearance following oral administration is approximately 6-7 L/h.

At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg KALETRA twice daily, and is similar between healthy volunteers and HIV-1 positive patients.

In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice daily with food for 3 weeks produced a mean SD lopinavir peak plasma concentration (Cmax) of 9.8 + or - 3.7 ug/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 + or - 2.9 ug/mL and minimum concentration within a dosing interval was 5.5 + or - 2.7 ug/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 + or - 36.7 ug*h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.

Anti-HIV Agents; HIV Protease Inhibitors

MEDICATION

Use (kg) in Switzerland (2009): >250