Ritonavir
Encyclopedia
Ritonavir, with trade name Norvir (Abbott Laboratories
), is an antiretroviral drug
from the protease inhibitor
class used to treat HIV
infection and AIDS
.
Ritonavir is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.
. Research that led to the drug's development was financed by a $3,500,000 federal grant
through the National Institutes of Health
(NIH) and over $200,000,000 by Abbott Labs. Most of the $200,000,000 figure cited by Abbott paid for clinical trials-despite NIH offering to pay for them-because Abbott was concerned about "public interest" responses to the high prices they projected Norvir would command. The Food and Drug Administration
(FDA) approved ritonavir on March 1, 1996, making it the seventh approved antiretroviral drug in the United States.
In 2003, Abbott raised the price of a Norvir course from USD
$1.71 per day to $8.57 per day, leading to claims of price gouging
by patients' groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004 that it lacked the legal right to allow generic production of Norvir.
Ritonavir was originally developed as an inhibitor of HIV protease. It is one of the most complex inhibitors. It is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitor
s, cytochrome P450-3A4
(CYP3A4). The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors.
This discovery, which has drastically reduced the adverse effects and improved the efficacy of PI's and HAART, was first communicated in an article published in the AIDS Journal
in 1997 by the University of Liverpool
. This effect does come with a price: it also affects the efficacy of numerous other medications, making it difficult to know how to administer them concurrently. In addition it can cause a large number of side-effects on its own.
s. These interactions can occur with strong inhibitors, strong or moderate inducers or substrates of hepatic cytochrome P450 CYP3A4
isoform.
The list of clinically significant interactions of ritonavir includes but is not limited to following drugs:
One of ritonavir's side effects is hyperglycemia
. It appears that ritonavir directly inhibits the GLUT4
insulin-regulated transporter, keeping glucose from entering fat and muscle cells. This can lead to insulin resistance
and cause problems for Type Ⅱ diabetics.
After this discovery in the late 1990s, Abbot withdrew the original capsules from the market, and recommended patients switch to Norvir suspension while researchers worked to solve the problem. The capsules have been replaced with refrigerated gelcaps, to solve the crystallization problem of the original capsules.
More recently Norvir has been reformulated into a white oblong solid tablet that no longer required refrigeration.
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
), is an antiretroviral drug
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
from the protease inhibitor
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
class used to treat HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection and AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
.
Ritonavir is frequently prescribed with HAART, not for its antiviral action, but as it inhibits the same host enzyme that metabolizes other protease inhibitors. This inhibition leads to higher plasma concentrations of these latter drugs, allowing the clinician to lower their dose and frequency and improving their clinical efficacy.
History
Ritonavir is manufactured as Norvir by Abbott LaboratoriesAbbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
. Research that led to the drug's development was financed by a $3,500,000 federal grant
Federal grant
In the United States, federal grants are economic aid issued by the United States government out of the general federal revenue. A federal grant is an award of financial assistance from a federal agency to a recipient to carry out a public purpose of support or stimulation authorized by a law of...
through the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) and over $200,000,000 by Abbott Labs. Most of the $200,000,000 figure cited by Abbott paid for clinical trials-despite NIH offering to pay for them-because Abbott was concerned about "public interest" responses to the high prices they projected Norvir would command. The Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) approved ritonavir on March 1, 1996, making it the seventh approved antiretroviral drug in the United States.
In 2003, Abbott raised the price of a Norvir course from USD
United States dollar
The United States dollar , also referred to as the American dollar, is the official currency of the United States of America. It is divided into 100 smaller units called cents or pennies....
$1.71 per day to $8.57 per day, leading to claims of price gouging
Price gouging
Price gouging is a pejorative term referring to a situation in which a seller prices goods or commodities much higher than is considered reasonable or fair. In precise, legal usage, it is the name of a crime that applies in some of the United States during civil emergencies...
by patients' groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004 that it lacked the legal right to allow generic production of Norvir.
Method of action
Protease inhibitor
Protease inhibitor can refer to:* Protease inhibitor : a class of medication that inhibits viral protease* Protease inhibitor : molecules that inhibit proteases...
s, cytochrome P450-3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
(CYP3A4). The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors.
This discovery, which has drastically reduced the adverse effects and improved the efficacy of PI's and HAART, was first communicated in an article published in the AIDS Journal
AIDS (journal)
AIDS is a peer-reviewed scientific journal that is published by Lippincott Williams & Wilkins . It was established in 1987 and is the official journal of the International AIDS Society. It covers all aspects of HIV and AIDS, including basic science, clinical trials, epidemiology, and social...
in 1997 by the University of Liverpool
University of Liverpool
The University of Liverpool is a teaching and research university in the city of Liverpool, England. It is a member of the Russell Group of large research-intensive universities and the N8 Group for research collaboration. Founded in 1881 , it is also one of the six original "red brick" civic...
. This effect does come with a price: it also affects the efficacy of numerous other medications, making it difficult to know how to administer them concurrently. In addition it can cause a large number of side-effects on its own.
Drug interactions
Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactionDrug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s. These interactions can occur with strong inhibitors, strong or moderate inducers or substrates of hepatic cytochrome P450 CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
isoform.
The list of clinically significant interactions of ritonavir includes but is not limited to following drugs:
- amiodaroneAmiodaroneAmiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
- decreased metabolism, possible toxicity - midazolamMidazolamMidazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
and triazolamTriazolamTriazolam is a benzodiazepine drug. It possesses pharmacological properties similar to that of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia...
- contraindicated - carbamazepineCarbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
- decreased metabolism, possible toxicity - cisaprideCisaprideCisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous...
- decreased metabolism, possible prolongation of Q-T interval and life-threatening arrythmias - disulfiramDisulfiramDisulfiram is a drug discovered in the 1920s and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals...
(with ritonavir oral preparation) - decreased metabolism of ritonavir - eplerenoneEplerenoneEplerenone is an aldosterone antagonist used as an adjunct in the management of chronic heart failure. It is similar to the diuretic spironolactone, though it may be more specific for the mineralocorticoid receptor and is specifically marketed for reducing cardiovascular risk in patients...
- etravirineEtravirineEtravirine is a drug used for the treatment of HIV. Etravirine is a non-nucleoside reverse transcriptase inhibitor . Unlike the currently available agents in the class, resistance to other NNRTIs does not seem to confer resistance to etravirine. Etravirine is marketed by Tibotec, a subsidiary...
- flecainideFlecainideFlecainide acetate is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias . It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation , paroxysmal supraventricular tachycardia Flecainide acetate is a class Ic antiarrhythmic agent used to...
- decreased metabolism, possible toxicity - MDMA
- meperidine - build-up of toxic concentrations of a metabolite possible
- nilotinibNilotinibNilotinib , in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor approved for the treatment of chronic myelogenous leukemia.-Uses:...
- nisoldipineNisoldipineNisoldipine is a calcium channel blocker of the dihydropyridine class. It sold in the United States under the proprietary name Sular. Nisoldipine has tropism for cardiac blood vessels....
- pimozidePimozidePimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
- quinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
- ranolazineRanolazineRanolazine, sold under the trade name Ranexa by Gilead Sciences , is an antianginal medication. In India it is sold under the name "Ranozex"...
- salmeterolSalmeterolSalmeterol is a long-acting beta2-adrenergic receptor agonist drug that is currently prescribed for the treatment of asthma and chronic obstructive pulmonary disease. It is currently available as a dry powder inhaler that releases a powdered form of the drug...
- St John's wortSt John's wortSt John's wort is the plant species Hypericum perforatum, and is also known as Tipton's Weed, Chase-devil, or Klamath weed....
- statinStatinStatins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s - decreased metabolism, without dosage modification increased risk of rhabomyolisis - thioridazineThioridazineThioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
- topotecanTopotecanTopotecan hydrochloride is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin...
- voriconazoleVoriconazoleVoriconazole is a triazole antifungal medication that is generally used to treat serious, invasive fungal infections. These are generally seen in patients who are immunocompromised, and include invasive candidiasis, invasive aspergillosis, and certain emerging fungal infections.-Invasive...
- ritonavir increases metabolism of voriconazole
Side effects
The most common side effects of ritonavir therapy are:- asthenia, malaise
- diarrhea
- nausea and vomiting
- abdominal pain
- dizziness
- insomnia
- sweating
- taste abonormality
- metabolic
- hypercholesterolemiaHypercholesterolemiaHypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
- hypertriglyceridemiaHypertriglyceridemiaIn medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
- elevated transaminaseTransaminaseIn biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. To be specific, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to the...
s - elevated CPKCreatine kinaseCreatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
- hypercholesterolemia
One of ritonavir's side effects is hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
. It appears that ritonavir directly inhibits the GLUT4
GLUT4
Glucose transporter type 4, also known as GLUT4, is a protein that in humans is encoded by the GLUT4 gene. GLUT4 is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose translocation into the cell...
insulin-regulated transporter, keeping glucose from entering fat and muscle cells. This can lead to insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
and cause problems for Type Ⅱ diabetics.
Conformational polymorphism
Norvir was originally dispensed as an ordinary capsule, which did not require refrigeration. The API of the original capsule exhibited strong conformational polymorphism. This threatened existing supplies of ritonavir as the lower energy polymorph caused the therapeutically effective polymorph to convert to the lower energy polymorph on contact. This lower energy polymorph, which was not therapeutically effective, entered production lines and effectively halted production processes.After this discovery in the late 1990s, Abbot withdrew the original capsules from the market, and recommended patients switch to Norvir suspension while researchers worked to solve the problem. The capsules have been replaced with refrigerated gelcaps, to solve the crystallization problem of the original capsules.
More recently Norvir has been reformulated into a white oblong solid tablet that no longer required refrigeration.
External links
- PubPK - Ritonavir pharmacokinetics
- Norvir (manufacturer's website)
- Ritonavir (patient information)