Apricitabine
Encyclopedia
Apricitabine is an experimental nucleoside reverse transcriptase inhibitor (NRTI) against HIV
. It is structurally related to lamivudine
and emtricitabine
, and, like these, is an analogue
of cytidine
.
, and has been granted fast track
status by the United States Food and Drug Administration.
Avexa announced its decision to end work on apricitabine in May 2010, which Avexa spent more than A$100 million ($90 million) developing and was in the final of three stages of patient studies usually needed for U.S. regulatory approval. Grounds for the shutdown included the inability to find commercial partners for global licencing, concerns about legal protections of the drug in the US market, and difficulty confirming the effectiveness of the drug in patients where other retroviral drugs masked key indicators.
In March 2011 it was announced by the company to the Australian Stock Exchange
that fast track approvals had been given by the FDA with Phase III trials to commence immediately, and that the company now held further hopes of reaching international partnership agreements to commercially produce the drug.
In November 2011 the company sought to extend its patents over apricitabine and was in discussions for fast-track approval with European regulators. The company also indicated that clinical trials had shown better-than-expected results from simultaneous provision of the drug alongside lamivudine
.
by up to 1.65 logs (45 fold) in a small, 10-day randomized controlled trial
.
s associated with its use were headache (although there was no significant
difference between participants who took apricitabine and those given a placebo
), nasal congestion
, and muscle pain. In a six-month trial, common adverse effects were nausea
, diarrhea
, elevated blood levels of triglycerides
, and upper respiratory infection—similar to those of lamivudine; apricitabine was not associated with abnormal lipase
levels, bone marrow suppression, or liver
and kidney
toxicity. No patients in either study had to stop taking apricitabine because of side effects.
)-resistant
viruses.
In early studies, no mutations causing drug resistance were observed. Newer trials showed that apricitabine may induce K65R mutations, resulting in resistance against didanosine
and tenofovir.
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...
. It is structurally related to lamivudine
Lamivudine
Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...
and emtricitabine
Emtricitabine
Emtricitabine , with trade name Emtriva , is a nucleoside reverse transcriptase inhibitor for the treatment of HIV infection in adults and children....
, and, like these, is an analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of cytidine
Cytidine
Cytidine is a nucleoside molecule that is formed when cytosine is attached to a ribose ring via a β-N1-glycosidic bond...
.
History
It was first developed by BioChem Pharma (where it was called BCH10618). BioChem Pharma was then sold to Shire Pharmaceuticals (where apricitabine was called SPD754). Shire then sold the rights to develop the drug to Avexa Pharmaceuticals, an Australian pharmaceutical company. , apricitabine has closed its phase III clinical trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
, and has been granted fast track
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
status by the United States Food and Drug Administration.
Avexa announced its decision to end work on apricitabine in May 2010, which Avexa spent more than A$100 million ($90 million) developing and was in the final of three stages of patient studies usually needed for U.S. regulatory approval. Grounds for the shutdown included the inability to find commercial partners for global licencing, concerns about legal protections of the drug in the US market, and difficulty confirming the effectiveness of the drug in patients where other retroviral drugs masked key indicators.
In March 2011 it was announced by the company to the Australian Stock Exchange
Australian Stock Exchange
The Australian Securities Exchange was created by the merger of the Australian Stock Exchange and the Sydney Futures Exchange in July 2006. It is the primary stock exchange group in Australia....
that fast track approvals had been given by the FDA with Phase III trials to commence immediately, and that the company now held further hopes of reaching international partnership agreements to commercially produce the drug.
In November 2011 the company sought to extend its patents over apricitabine and was in discussions for fast-track approval with European regulators. The company also indicated that clinical trials had shown better-than-expected results from simultaneous provision of the drug alongside lamivudine
Lamivudine
Lamivudine is a potent nucleoside analog reverse transcriptase inhibitor .It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-HBV.Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment of HIV...
.
Dosage
As a monotherapy, 1200 mg apricitabine per day reduced the viral loadViral load
Viral load is a measure of the severity of a viral infection, and can be calculated by estimating the amount of virus in an involved body fluid. For example, it can be given in RNA copies per milliliter of blood plasma...
by up to 1.65 logs (45 fold) in a small, 10-day randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
.
Adverse effects
Apricitabine appears to be well tolerated. The most common side effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s associated with its use were headache (although there was no significant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
difference between participants who took apricitabine and those given a placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
), nasal congestion
Nasal congestion
Nasal congestion is the blockage of the nasal passages usually due to membranes lining the nose becoming swollen from inflamed blood vessels. It is also known as nasal blockage, nasal obstruction, blocked nose, stuffy nose, or stuffed up nose.Nasal congestion has many causes and can range from a...
, and muscle pain. In a six-month trial, common adverse effects were nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, elevated blood levels of triglycerides
Hypertriglyceridemia
In 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,...
, and upper respiratory infection—similar to those of lamivudine; apricitabine was not associated with abnormal lipase
Lipase
A lipase is an enzyme that catalyzes the formation or cleavage of fats . Lipases are a subclass of the esterases.Lipases perform essential roles in the digestion, transport and processing of dietary lipids in most, if not all, living organisms...
levels, bone marrow suppression, or liver
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
and kidney
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
toxicity. No patients in either study had to stop taking apricitabine because of side effects.
Drug resistance
In vitro, apricitabine was effective against NRTI-(lamivudine and zidovudineZidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
)-resistant
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
viruses.
In early studies, no mutations causing drug resistance were observed. Newer trials showed that apricitabine may induce K65R mutations, resulting in resistance against didanosine
Didanosine
Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy .-History:The related pro-drug of didanosine,...
and tenofovir.