Lopinavir/ritonavir (LPV/r), sold under the brand name Kaletra among others, is a

fixed-dose combination A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

antiretroviral medication The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mul ...

for the treatment and prevention of

HIV/AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

. It combines

lopinavir Lopinavir is an anti retroviral of the protease inhibitor class. It is used against HIV infections as a fixed-dose combination with another protease inhibitor, ritonavir (lopinavir/ritonavir). It was patented in 1995 and approved for medica ...

with a low dose of

ritonavir Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhi ...

. It is generally recommended for use with other

antiretrovirals The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of mul ...

. It may be used for prevention after a

needlestick injury A needlestick injury is the penetration of the skin by a hypodermic needle or other sharp object that has been in contact with blood, tissue or other body fluids before the exposure. Even though the acute physiological effects of a needlestick ...

or other potential exposure. It is taken by mouth as a tablet, capsule, or solution. Common side effects include

diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...

, vomiting, feeling tired, headaches, and muscle pains. Severe side effects may include

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

liver problems Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...

, and

high blood sugar Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluco ...

. It is commonly used in

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

and it appears to be safe. Both medications are

HIV protease inhibitors The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...

. Ritonavir functions by slowing down the breakdown of lopinavir. Lopinavir/ritonavir as a combination medication was approved for use in the United States in 2000. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

Medical uses

Lopinavir/ritonavir was once a preferred combination for HIV first-line therapy in the United States. But due to its higher pill burden compared to other protease inhibitor-based regimens and increased gastrointestinal intolerance, it is no longer recommended to treatment-naive patients.

Adverse effects

The most common adverse effects observed with lopinavir/ritonavir are

and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

. In key clinical trials, moderate or severe diarrhea occurred in up to 27% of patients, and moderate/severe nausea in up to 16%. Other common adverse effects include

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

asthenia Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

and, particularly in children,

rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

. Lopinavir/ritonavir is anticipated to have varying degrees of interaction with other medications that are also

CYP3A Cytochrome P450, family 3, subfamily A, also known as CYP3A, is a human gene locus. A homologous locus is found in mice. These genes encode monooxygenases which catalyze many reactions involved in the synthesis of cholesterol, steroids and other ...

and/or

P-gp P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

substrates. People with a structural

heart disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina pectoris, angina, myocardial infarction, heart attack), heart failure, ...

, preexisting conduction system abnormalities,

ischaemic heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the a ...

, or

cardiomyopathies Cardiomyopathy is a group of primary diseases of the heart muscle. Early on there may be few or no symptoms. As the disease worsens, shortness of breath, feeling tired, and swelling of the legs may occur, due to the onset of heart failure. An ...

should use lopinavir/ritonavir with caution. In March 2011, the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) notified healthcare professionals of serious health problems that have been reported in premature babies receiving lopinavir/ritonavir oral solution, probably because of its

propylene glycol Propylene glycol ( IUPAC name: propane-1,2-diol) is a viscous, colorless liquid. It is almost odorless and has a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. As it contains two alcohol groups, it is classified as a diol. An al ...

content. They recommend the use should be avoided in premature babies.

History

Abbott Laboratories Abbott Laboratories is an American multinational medical devices and health care company with headquarters in Abbott Park, Illinois, in the United States. The company was founded by Chicago physician Wallace Calvin Abbott in 1888 to formulate k ...

(now, via spinoff,

Abbvie AbbVie Inc. is an American pharmaceutical company headquartered in North Chicago, Illinois. It is ranked sixth on the list of largest biomedical companies by revenue. In 2023, the company's seat in Forbes Global 2000 was 74, and rank 89 on the ...

) was one of the earliest users of the

Advanced Photon Source The Advanced Photon Source (APS) at Argonne National Laboratory (in Lemont, Illinois) is a storage-ring-based high-energy X-ray light source facility. It is one of five X-ray light sources owned and funded by the U.S. Department of Energy Office ...

(APS), a national synchrotron-radiation light source at

Argonne National Laboratory Argonne National Laboratory is a Federally funded research and development centers, federally funded research and development center in Lemont, Illinois, Lemont, Illinois, United States. Founded in 1946, the laboratory is owned by the United Sta ...

. One of the early research projects undertaken at the APS focused on proteins from the human immunodeficiency virus (HIV). Using the APS beam line for

X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...

, researchers determined viral protein structures that allowed them to determine their approach to the development of HIV protease inhibitors, a key enzyme target that processes HIV polyproteins after infection, the function of which allows the lifecycle of the virus to proceed. As a result of this

structure-based drug design Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activ ...

approach using the Argonne APS, Abbott was able to develop new products that inhibit the protease, and therefore stop virus replication. Lopinavir was developed by Abbott in an attempt to improve upon the company's earlier protease inhibitor, ritonavir, specifically with regard to its serum protein-binding properties (reducing the interference by serum on protease enzyme inhibition) and its HIV resistance profile (reducing the ability of virus to evolve resistance to the drug). Administered alone, lopinavir has insufficient

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

; however, like several HIV protease inhibitors, its blood levels are greatly increased by low doses of ritonavir, a potent inhibitor of intestinal and hepatic

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

3A4, which would otherwise reduce drug levels through

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...

. Lopinavir/ritonavir was approved by the US

(FDA) in September 2000, and in the European Union in March 2001. In March 2020, during the

COVID-19 pandemic The COVID-19 pandemic (also known as the coronavirus pandemic and COVID pandemic), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began with an disease outbreak, outbreak of COVID-19 in Wuhan, China, in December ...

, the

Israeli government The Israeli system of government is based on parliamentary democracy. The Prime Minister of Israel is the head of government and leader of a multi-party system. Executive power is exercised by the government (also known as the cabinet). Legislat ...

announced that it would force AbbVie to license its patents for lopinavir/ritonavir. In response, AbbVie announced that it would cease enforcing its patents on the drug entirely.

Society and culture

Cost

As a result of high prices and the spread of HIV infection, the government of

Thailand Thailand, officially the Kingdom of Thailand and historically known as Siam (the official name until 1939), is a country in Southeast Asia on the Mainland Southeast Asia, Indochinese Peninsula. With a population of almost 66 million, it spa ...

issued a

compulsory license A compulsory license provides that the owner of a patent or copyright licenses the use of their rights against payment either set by law or determined through some form of adjudication or arbitration. In essence, under a compulsory license, an i ...

in January 2007, to produce and/or import

generic Generic or generics may refer to: In business * Generic term, a common name used for a range or class of similar things not protected by trademark * Generic brand, a brand for a product that does not have an associated brand or trademark, other ...

versions of lopinavir and ritonavir. In response, Abbott Laboratories withdrew its registration for lopinavir and seven of their other new drugs in Thailand, citing the Thai government's lack of respect for

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

s. Abbott's attitude has been denounced by several

NGO A non-governmental organization (NGO) is an independent, typically nonprofit organization that operates outside government control, though it may get a significant percentage of its funding from government or corporate sources. NGOs often focus ...

s worldwide, including a netstrike initiated by Act Up-Paris and a public call to

boycott A boycott is an act of nonviolent resistance, nonviolent, voluntary abstention from a product, person, organisation, or country as an expression of protest. It is usually for Morality, moral, society, social, politics, political, or Environmenta ...

all of Abbott's medicines by the French NGO

AIDES Aides may refer to: * AIDES, a French non-governmental organization assisting people with HIV/AIDS * ''Aides'' (skipper), a genus of skippers of family Hesperiidae * Aides (tax), a French customs duty during the time of Louis XIV *Hades, a Greek ...

Available forms

Heat-stable pellets that can be taken by mouth have been developed for children.

Research

While data for

SARS-CoV-1 Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), previously known as severe acute respiratory syndrome coronavirus (SARS-CoV), is a strain (biology), strain of coronavirus that causes severe acute respiratory syndrome (SARS), the ...

looked promising, the benefit in

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...

is unclear as of March 2020. In 2020, a non-blinded, randomized trial found lopinavir/ritonavir was not useful to treat severe

. In this trial the medication was started typically around 13 days after the start of symptoms.

References

External links

* {{DEFAULTSORT:Lopinavir Ritonavir CYP3A4 inhibitors Fixed dose combination (antiretroviral) Hepatotoxins Drugs developed by AbbVie World Health Organization essential medicines Wikipedia medicine articles ready to translate HIV protease inhibitors