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

antiretroviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...

for the treatment and prevention of

HIV/AIDS Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...

. It combines

lopinavir Lopinavir is an antiretroviral 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 drug used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor ...

. 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 multiple ...

. It may be used for prevention after a needlestick injury or other potential exposure. It is taken by mouth as a tablet, capsule, or solution. Common side effects include

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...

, 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 hormones. There are two main types: acute pancreatitis, and chronic p ...

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. Signs and symptoms Some of the s ...

, and

high blood sugar Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

. It is commonly used in

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

and it appears to be safe. Both medications are

HIV protease inhibitors Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replicat ...

. Ritonavir functions by slowing down the breakdown of lopinavir. Lopinavir/ritonavir as a single medication was approved for use in the United States in 2000. It is on the World Health Organization's List of Essential Medicines.

Medical uses

Lopinavir/ritonavir was once a preferred combination for HIV first-line therapy in the United States. But due its higher pill burden compared to than 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. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

. 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. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...

asthenia Weakness is a symptom of a number of different 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, i ...

headache Headache 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 in those with severe headaches. Headaches can occur as a result ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, 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, gastroenter ...

and, particularly in children,

rash A rash is a change of the human skin which 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, c ...

. Raised liver enzymes and

hyperlipidemia Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...

(both

hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and ...

and

hypercholesterolemia Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...

) are also commonly observed during lopinavir/ritonavir treatment. Lopinavir/ritonavir is anticipated to have varying degrees of interaction with other medications that are also CYP3A 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 a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...

, preexisting conduction system abnormalities,

ischaemic heart disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pla ...

, or cardiomyopathies should use lopinavir/ritonavir with caution. On 8 March 2011 the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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, which is nearly odorless but possesses a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. Containing two alcohol groups, it is classed as a diol. It ...

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, United States. The company was founded by Chicago physician Wallace Calvin Abbott in 1888 to formulate known dr ...

(now, via spinoff,

Abbvie AbbVie is an American publicly traded biopharmaceutical company founded in 2013. It originated as a spin-off of Abbott Laboratories. History On October 19, 2011, Abbott Laboratories announced its plan to separate into two publicly traded compani ...

) 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 o ...

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

Argonne National Laboratory Argonne National Laboratory is a science and engineering research national laboratory operated by UChicago Argonne LLC for the United States Department of Energy. The facility is located in Lemont, Illinois, outside of Chicago, and is the l ...

. 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 determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...

, 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%. Ho ...

; 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 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

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, li ...

. Abbott, therefore, pursued a strategy of co-administering lopinavir with doses of ritonavir sub-therapeutic with respect to HIV inhibition; hence, lopinavir was only formulated and marketed as a fixed-dose combination medication with ritonavir. Lopinavir/ritonavir was approved by the US

(FDA) on 15 September 2000, and in Europe on 19 March 2001. Its patent was scheduled to expire in the US on 26 June 2016. In March 2020, during the

COVID-19 pandemic The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identi ...

, the

Israeli government The Cabinet of Israel (officially: he, ממשלת ישראל ''Memshelet Yisrael'') exercises executive authority in the State of Israel. It consists of ministers who are chosen and led by the prime minister. The composition of the governmen ...

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 ( ), historically known as Siam () and officially the Kingdom of Thailand, is a country in Southeast Asia, located at the centre of the Indochinese Peninsula, spanning , with a population of almost 70 million. The country is b ...

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 ...

on 29 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 enabling disclosure of the invention."A ...

s. Abbott's attitude has been denounced by several NGOs worldwide, including a netstrike initiated by Act Up-Paris and a public call to

boycott A boycott is an act of nonviolent, voluntary abstention from a product, person, organization, or country as an expression of protest. It is usually for moral, social, political, or environmental reasons. The purpose of a boycott is to inflict so ...

all of Abbott's medicines by the French NGO AIDES.

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; or Severe acute respiratory syndrome coronavirus, SARS-CoV) is a strain of coronavirus that causes severe acute respiratory syndrome (SARS), the respiratory illness responsible for t ...

looked promising, the benefit in

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quick ...

is unclear as of 23 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 AbbVie brands World Health Organization essential medicines Wikipedia medicine articles ready to translate HIV protease inhibitors