192725-17-0

Lopinavir, the sixth HIV protease inhibitor in the “navir” class, was launched in coformulation with ritonavir, another HIV protease inhibitor already marketed (Abbott, 1996); this original formulation was introduced as Kaletra for use in combination with either nucleoside or non-nucleoside reverse transcriptase inhibitors for the treatment of AIDS in adults and children. Lopinavir is a peptidomimetic compound with a structural core identical to that of ritonavir, on which terminal groups, particularly a modified valine, were introduced by peptide coupling procedures. Lopinavir is a potent competitive inhibitor of HIV-I protease exhibiting high potential against ritonavir-resistant mutations. In several animal species, pharmacokinetic studies with the lopinavirlritonavir association showed that the modest properties of lopinavir were significantly improved in presence of ritonavir, in terms of Cmax and duration of action. Ritonavir inhibits the P450 isoenzyme CYP3A4 and the human liver microsomal metabolism of lopinavir, so strongly amplifying plasma levels of this latter component. In AIDS patients, the plasma HIV RNA level was considerably reduced and the CD4+ T-cell counts increased after administration of lopinavir combined with relatively small doses of ritonavir. Kaletra is intended to be used jointly with other antiretroviral agents.

White Crystalline Solid

Abbott (US)

A selective HIV protease inhibitor. An analogue of Ritonavir. Antiviral.

Lopinavir is a potent HIV protease inhibitor with Ki of 1.3 pM

ChEBI: A dicarboxylic acid amide in which a parent structure of amphetamine is substituted on nitrogen by a (2,6-dimethylphenoxy)acetyl group and on the carbon alpha to nitrogen by a (1S,3S)-1-hydroxy-3-{[(2S)-3- ethyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl group. An antiretroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir.

Lopinavir is available in the United States only as a fixed-dose combination with ritonavir (Kaletra). In this regimen, a low dose of ritonavir is used to inhibit the rapid inactivation of lopinavir by CYP3A4.

Manufacturing process for Lopinavir includes these steps as follows: Synthesis of 2,6-dimethylphenoxyacetic acid; 2,6- dimethylphenoxyacetyl chloride as an oil; synthesis of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5-(tbutyloxycarbonylamino)-1,6-diphenylhexane; (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5- amino-1,6-diphenylhexane as a white needles; synthesis of N-carbonylbenzyloxy-3- aminopropanol;synthesis of N-carbonylbenzyloxy-3-aminopropanal solution; N-(N- (benzyloxycarbonyl-3-amino)-propyl)valine methyl ester, oil state; synthesis of 2S-(1-tetrahydro-pyrimid-2-onyl)-3- methyl butanoic acid methyl ester;synthesis of 2S-(1- tetrahydro-pyrimid-2-onyl)-3-methyl butanoic acid methyl ester. The mixture of (2S,3S,5S)-2-(2,6-dimethylphenoxyacetyl)amino-3-hydroxy-5- amino-1,6-diphenylhexane (100 g, 0.22 mol), 2S-(1-tetrahydro-pyrimid-2- onyl)-3-methyl butanoic acid methyl ester (44.8 g, 0.22 mol) and 750 ml DMF was cooled in an ice/water bath. N-Hydroxybenzotriazole (90.9 g, 0.67 mol), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide (86 g, 0.45 mol) and triethylamine (62.5 ml, 0.45 mol) were added and the ice bath was removed, allowing the reaction mixture to stir with warming to room temperature for 5 hours. The mixture was diluted with 1000 ml of IPAC and quenched with 1000 ml of water. The mixture was shaken and separated, the aq. layer was extracted IPAC, the organics were washed with 10% HCl, solution of NaHCO3 with 100 ml hexanes, then washed 500 ml water, and brine, dried over MgSO4, filtered and concentrated to provide. (2S,3S,5S)-2-(2,6- dimethylphenoxyacetyl)amino-3-hydroxy-5-(2S-(1-tetrahydro-pyrimid-2-onyl)- 3-methylbutanoyl)amino-1,6-diphenylhexane as a white foam.

Kaletra

Antiviral

Lopinavir is active against HIV-1 and HIV-2.

Significant resistance to the antiretroviral efficacy of ritonavirbooted lopinavir occurs as a result of amino acid substitutions at positions 32, 47 and 82 in the protease region. Protease inhibitor resistance is uncommon in patients identified with early failure of combination therapy with ritonavir boostedlopinavir and nucleotide reverse transcriptase inhibitors.

Lopinavir is a protease inhibitor that has been approved foruse in combination with ritonavir for patients with HIV whohave not responded to other treatment modalities. Lopinaviris used in excess over ritonavir. Ritonavir at amounts givenhas no antiretroviral activity, Ritonavir inhibits lopinavir’smetabolism by CYP3A4, causing a higher level of lopinavirin the system. The combination is the first protease inhibitorapproved for patients as young as 6 months of age.

A synthetic compound, co-formulated with ritonavir for oral administration. In this formulation, ritonavir functions to inhibit the metabolic clearance of lopinavir, and does not contribute to the antiretroviral activity.

Lopinavir is an antiviral HIV Protease Inhibitor. Lopinavir has insufficient bioavailability alone, so it is used in therapy in combination with Ritonavir, a HIV protease inhibitor, which inhibits cytochrome P450-3A4 (CYP3A4), a liver enzyme that normally metabolizes protease inhibitors. Lopinavir also has an ability to inhibit ZMPSTE24 (zinc metallopeptidase STE24).

Oral absorption: Not known/available
C_max 400 mg + ritonavir 100 mg twice daily: c. 9.6 mg/L
C_min 400 mg + ritonavir 100 mg twice daily: c. 5.5 mg/L
Plasma half-life: c. 5–6 h
Volume of distribution: Not known/available
Plasma protein binding: c. 98–99%
Absorption and distribution
The absorption of lopinavir–ritonavir in capsule or liquid form is favorably affected by the presence of food, particularly if high in fat. The CNS penetration is good. It has a semen:plasma ratio of 0.07. It is distributed into breast milk.
Metabolism
Lopinavir is extensively metabolized by the CYP3A4 system, but this is inhibited by ritonavir.
Excretion
Over an 8-day period after single dosing with the combined formulation, around 10% and 83% of the administered dose is recovered in urine and feces, respectively. Less than 3% of the dose is recovered as unchanged drug in urine and 20% in feces. In mild to moderate hepatic impairment, an increase in exposure of approximately 30% is observed, but is probably not clinically relevant. It should be avoided in severe hepatic impairment.

Treatment of HIV infection (in combination with ritonavir and other antiretroviral agents)

Side effects, which are generally mild, include diarrhea, nausea, asthenia, and headache. Pancreatitis occurs rarely. Ritonavir is a potent inhibitor of CYP3A4 and also inhibits CYP2D6. In addition to the drugs contraindicated for all protease inhibitors, flecainide, propafenone, pimozide, and rifampin should not be given with lopinavir–ritonavir combination therapy.

The most common adverse events seen in trials of complex antiretroviral regimens were diarrhea, nausea, headache, fatigue, vomiting and rash. Ritonavir-boosted lopinavir is associated with a dyslipidemia profile characteristic of those treated with other protease inhibitors boosted with 200 mg of ritonavir.

HIV protease

Potentially hazardous interactions with other drugs In combination with ritonavir - see ritonavir interactions. Anti-arrhythmics: increased risk of ventricular arrhythmias with flecainide - avoid; possibly increased lidocaine concentration. Antibacterials: concentration reduced by rifampicin - avoid; concentration of delamanid increased; avoid with telithromycin in severe renal and hepatic impairment; AUC of bedaquiline increased by 22%, avoid. Anticoagulants: avoid with apixaban and rivaroxaban. Antidepressants: concentration reduced by St John’s wort - avoid. Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenytoin, primidone and phenobarbital. Antimalarials: use artemether/lumefantrine with caution. Antipsychotics: possibly inhibits metabolism of aripiprazole - reduce dose of aripiprazole; possibly increases quetiapine concentration - avoid. Antivirals: avoid with boceprevir, daclatasvir and telaprevir; concentration of darunavir and fosamprenavir reduced - avoid; in combination with ritonavir concentration of elvitegravir increased - reduce dose of elvitegravir; concentration reduced by efavirenz, tipranavir and possibly nevirapine, consider increasing lopinavir dose; concentration of paritaprevir increased - avoid; increased risk of ventricular arrhythmias with saquinavir - avoid; concentration of tenofovir increased; concentration of maraviroc increased, consider reducing maraviroc dose. Bosentan: concentration of bosentan increased, consider reducing bosentan dose. Ciclosporin: may increase concentration of ciclosporin. Cytotoxics: reduce dose of ruxolitinib. Lipid lowering agents: increased risk of myopathy with atorvastatin; possibly increased risk of myopathy with rosuvastatin (reduce rosuvastatin dose) and simvastatin - avoid; avoid with lomitapide. Orlistat: absorption of lopinavir possibly reduced. Ranolazine: possibly increases ranolazine concentration - avoid. Sirolimus: may increase concentration of sirolimus. Tacrolimus: may increase concentration of tacrolimus.

Lopinavir is extensively metabolised, mainly by oxidation by cytochrome P450 isoenzyme CYP3A4; 13 metabolites have been identified with some, such as 4-oxylopinavir and 4-hydroxylopinavir, having antiviral activity. Lopinavir is mainly excreted in faeces and to a smaller extent in the urine; unchanged lopinavir accounts for about 2.2% of a dose excreted in the urine and 19.8% in the faeces. After multiple dosing, less than 3% of the absorbed lopinavir dose is excreted unchanged in the urine

Store at -20°C