Lopinavir

(BAN, USAN, rINN)
Lopinavir Chemical formula
Synonyms: A-157378.0; ABT-378; Lopinaviiri; Lopinavirum. ( N-(( mido]butyl}phenethyl)cetamide.
Cyrillic synonym: Лопинавир.

💊 Chemical information

Chemical formula: C37H48N4O5 = 628.8.
CAS — 192725-17-0.
ATC — J05AE06.
ATC Vet — QJ05AE06.

💊 Adverse Effects

The most common adverse effect associated with antiretroviral regimens containing lopinavir (formulated with ritonavir) is diarrhoea of mild to moderate severity. Pancreatitis has been seen in patients receiving lopinavir, including those who developed marked triglyceride elevations; in some cases fatalities have occurred. Other commonly reported adverse effects include asthenia, headache, insomnia, pain, paraesthesia, gastrointestinal disturbances, acne, and rash. Abnormal laboratory test results associated with lopinavircontaining regimens include increases in serum cholesterol and triglycerides and raised liver enzymes. Immune reconstitution syndrome (an inflammatory immune response resulting in clinical deterioration) has been reported during the initial phase of treatment with combination antiretroviral therapy, including lopinavir, in HIV-infected patients with severe immune deficiency. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been seen in patients receiving antiretroviral therapy, including lopinavir. Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia have also been reported. Elevated creatine phosphokinase, myalgia, myositis, and rarely rhabdomyolysis have been reported with HIVprotease inhibitors, particularly when given with nucleoside analogues. Osteonecrosis has been reported, particularly in patients with advanced HIV disease or long-term exposure to combination antiretroviral therapy. For further information on adverse effects associated with HIV-protease inhibitors see under Indinavir Sulfate.

💊 Precautions

Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during treatment with ritonavir-boosted lopinavir. Such therapy should be stopped if symptoms of pancreatitis occur. The oral solution (Kaletra, Abbott) has a high content of alcohol and propylene glycol, present as excipients, and appropriate precautions should be taken; it is contra-indicated in infants and young children, in pregnancy, and in hepatic or renal impairment. For further information on propylene glycol toxicity, see Adverse Effects and Precautions.

Pregnancy.

Licensed product information notes that in rats given toxic doses of ritonavir-boosted lopinavir, there was early resorption, decreased fetal viability and body weight, and an increased incidence of skeletal variation and delayed skeletal ossification in the offspring.

💊 Interactions

Lopinavir is extensively metabolised by the cytochrome P450 isoenzyme CYP3A4. It is formulated with low-dose ritonavir, which inhibits this enzyme and thus increases exposure. The combination is an inhibitor of CYP3A4 and increases plasma concentration of drugs mainly metabolised by this isoenzyme. It has also been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolised by cytochrome P450 isoenzymes and by glucuronidation. Drugs that strongly induce CYP3A4 may result in decreased plasma concentrations of the combination. Ritonavir-boosted lopinavir is contra-indicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious or life-threatening events. These drugs include antihistamines (astemizole and terfenadine), ergot derivatives (dihydroergotamine, ergometrine, ergotamine, and methylergometrine), gastrointestinal prokinetics (cisapride), antipsychotics (pimozide), sedatives and hypnotics (midazolam and triazolam), and statins (simvastatin and lovastatin). Rifampicin and St John’s wort decrease the concentration of lopinavir; use with the antiretroviral is not recommended due to the possible loss of its activity and development of resistance. UK licensed product information contra-indicates the use of vardenafil and amiodarone with ritonavir-boosted lopinavir.

💊 Antiviral Action

Lopinavir is a selective, competitive, reversible inhibitor of HIV-1 protease. It interferes with the formation of essential viral proteins making them incapable of infecting other cells. Viral resistance develops rapidly when HIV-protease inhibitors are given alone and therefore they are used with other antiretrovirals. Various degrees of cross-resistance between HIV-protease inhibitors may occur.

💊 Pharmacokinetics

Lopinavir is rapidly absorbed from the gastrointestinal tract after oral doses, with peak plasma concentrations occurring after 4 hours. Bioavailability is enhanced when given with a high fat meal. Lopinavir is reported to be 98 to 99% bound to serum proteins. 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 predominantly 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. The terminal elimination half-life of lopinavir is reported to be about 5 to 6 hours.
1. Jullien V, et al. Population analysis of weight-, age-, and sexrelated differences in the pharmacokinetics of lopinavir in children from birth to 18 years. Antimicrob Agents Chemother 2006; 50: 3548–55.

💊 Uses and Administration

Lopinavir is an HIV-protease inhibitor with antiviral activity against HIV. It is formulated with low-dose ritonavir, which acts as a pharmacokinetic enhancer. The combination is used in the treatment of HIV infection and AIDS. Ritonavir-boosted lopinavir is also recommended for HIV postexposure prophylaxis. Viral resistance emerges rapidly when ritonavir-boosted lopinavir is used alone, and it is therefore used with other antiretrovirals. The dose in treatment-naive and -experienced adults is lopinavir 400 mg (with ritonavir 100 mg) twice daily. Alternatively, treatment-naive patients may take a once-daily dose of lopinavir 800 mg (with ritonavir 200 mg). US licensed product information recommends that if the tablets are given in a treatment regimen with either amprenavir, fosamprenavir, nelfinavir, efavirenz, or nevirapine in treatment-experienced patients consideration be given to increasing the dose of lopinavir to 600 mg (with ritonavir 150 mg) twice daily. For patients taking the oral solution in such regimens the dose should be increased to lopinavir 533 mg (with ritonavir 133 mg) twice daily. Lopinavir film-coated tablets may be taken with or without food; the soft capsules and solution should be taken with food. For details of doses in children, see below.
1. Oldfield V, Plosker GL. Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs 2006; 66: 1275–99.

Administration in children.

For the treatment of HIV infection in children, ritonavir-boosted lopinavir is given daily with other antiretroviral drugs. The US licensed product information permits use in infants as young as 14 days old, whereas in the UK the age is 2 years. The dose given should not exceed the maximum adult dose (see above). In the UK the use of the oral solution is preferred to the soft capsules as a more accurate dose may be given. Doses are based on body-surface.
In children 2 years of age or more the recommended dose of the oral solution is lopinavir 230 mg/m2 (with ritonavir 57.5 mg/m2) twice daily with food. The dose should be increased to 300 mg/m2 (with ritonavir 75 mg/m2) twice daily with food when given with efavirenz or nevirapine
The recommended dose of the oral soft capsules in children is according to body-surface as follows:
0.40 to 0.75 m2: lopinavir 133.3 mg (with ritonavir 33.3 mg) twice daily
0.80 to 1.3 m2: lopinavir 266.6 mg (with ritonavir 66.6 mg) twice daily
1.4 to 1.75 m2: lopinavir 400 mg (with ritonavir 100 mg) twice daily In the USA the dose is based on body-weight or body-surface as follows:
given without interacting antiretrovirals
14 days to 6 months of age: lopinavir 16 mg/kg (with ritonavir 4 mg/kg) twice daily or lopinavir 300 mg/m2 (with ritonavir 75 mg/m2) twice daily
6 months or older and less than 15 kg: lopinavir 12 mg/kg (with ritonavir 3 mg/kg) twice daily or lopinavir 230 mg/m2 (with ritonavir 57.5 mg/m2) twice daily
15 to 40 kg: lopinavir 10 mg/kg (with ritonavir 2.5 mg/kg) twice daily or lopinavir 230 mg/m2 (with ritonavir 57.5 mg/m2) twice daily
over 40 kg: normal adult dose
given in a treatment regimen with either amprenavir, fosamprenavir, efavirenz, nelfinavir, or nevirapine (requiring the dose of lopinavir/ritonavir to be increased):
6 months or older and less than 15 kg: lopinavir 13 mg/kg (with ritonavir 3.25 mg/kg) twice daily or lopinavir 300 mg/m2 (with ritonavir 75 mg/m2) twice daily
15 to 45 kg: lopinavir 11 mg/kg (with ritonavir 2.75 mg/kg) twice daily or lopinavir 300 mg/m2 (with ritonavir 75 mg/m2) twice daily
over 45 kg: as for adults, above

SARS.

In a preliminary open study1 41 patients with probable SARS were given ritonavir-boosted lopinavir as well as the local standard treatment of ribavirin and corticosteroids. At 21 days there was improved outcome with reductions in viral load, corticosteroid dose, and the incidence of nosocomial infections.
1. Chu CM, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004; 59: 252–6.

💊 Preparations

Proprietary Preparations

Multi-ingredient: Arg.: Kaletra; Austral.: Kaletra; Austria: Kaletra; Belg.: Kaletra; Braz.: Kaletra; Canad.: Kaletra; Chile: Kaletra; Cz.: Kaletra; Denm.: Kaletra; Fin.: Kaletra; Fr.: Kaletra; Ger.: Kaletra; Gr.: Kaletra; Hong Kong: Kaletra; Hung.: Kaletra; India: Ritomax-L; Israel: Kaletra; Ital.: Kaletra; Malaysia: Kaletra; Mex.: Kaletra; Neth.: Kaletra; Norw.: Kaletra; NZ: Kaletra; Pol.: Kaletra; Port.: Kaletra; Rus.: Kaletra (Калетра); S.Afr.: Kaletra; Singapore: Kaletra; Spain: Kaletra; Swed.: Kaletra; Switz.: Kaletra; Thai.: Kaletra; Turk.: Kaletra; UK: Kaletra; USA: Kaletra; Venez.: Kaletra.
Published December 04, 2018.