Abacavir

Structural formula
(1 S , 4 R ) isomer
General
Non-proprietary name	Abacavir
other names	(1 S , 4 R ) -4- [2-Amino-6- (cyclopropylamino) -9 H -purin-9-yl] -2-cyclopentene-1-methanol (1 S , 4 R ) -4- [2-Amino-6- (cyclopropylamino) -9 H -purin-9-yl] cyclopent-2-en-1-methanol
Molecular formula	C 14 H 18 N 6 O (abacavir) (C 14 H 18 N 6 O) 2 · H 2 SO 4 (2 Abacavir · H 2 SO 4 )
External identifiers / databases
CAS number 136470-78-5 (abacavir) 188062-50-2 (2 abacavir · H 2 SO 4 ) 168146-84-7 (abacavir succinate ) EC number 620-487-9 ECHA InfoCard 100.149.341 PubChem 441300 ChemSpider 390063 DrugBank DB01048 Wikidata Q304330
Drug information
ATC code	J05 AF06
Drug class	Antiviral agent , nucleoside reverse transcriptase inhibitors
Mechanism of action	Competitive inhibition of reverse transcriptase
properties
Molar mass	286.33 g · mol -1 (abacavir) 670.74 g · mol -1 (2 abacavir · H 2 SO 4 )
Physical state	firmly
Melting point	165 ° C (abacavir)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Abacavir is a medicine used to treat HIV-1 infected patients as part of combination antiretroviral therapy . As a nucleoside analog, it belongs to the group of carbocyclic, nucleoside reverse transcriptase inhibitors (NRTIs). The suffix -cavir describes a carbocyclic nucleoside .

A special feature is that therapy with abacavir is linked to a previous genetic test . This test checks for the presence of the gene marker HLA-B * 57: 01 . A potentially life-threatening hypersensitivity reaction occurs in up to 80% of patients with this gene marker.

pharmacology

Pharmacodynamics

Abacavir is first converted into the triphosphate . In addition, the base portion is metabolized. Carbovir triphosphate is produced as a biologically active metabolic product . This inhibits reverse transcriptase . In vitro it works partially synergistically with nucleosides and HIV protease inhibitors .

Pharmacokinetics

The bioavailability is over 70%. The elimination half-life is given as about 1.5 hours. For the active triphosphate, the intracellular half-life is given as 3 to 4 hours. It is taken in two single doses of 300 mg daily. Food delays absorption and lowers the maximum plasma concentration. However, since the AUC value is not influenced and therefore the therapy is not impaired, it can be taken independently of meals. With regular use, maximum levels of (3.0 ± 0.9) mg / l are given; the AUC value was calculated as (6.0 ± 1.7) mg / l × h. The concentration in the CSF corresponds to about one third of the plasma concentration . Abacavir is predominantly (approximately 85%) metabolized and excreted in the urine. The drug is not metabolized by the cytochrome P450 system . There is no corresponding potential for interaction. Abacavir is primarily biotransformed in the liver via alcohol dehydrogenase .

Side effects

The most important side effect is a hypersensitivity reaction (approx. 5%). Symptoms: fever , rash , fatigue and gastrointestinal symptoms. The symptoms usually appear between the first and fourth week of treatment. After stopping the drug, the symptoms subside within one to two days. Abacavir should not be administered again after this. A severe, life-threatening hypersensitivity reaction with a drop in blood pressure occurred more frequently within one to two hours. Lactic acidosis and hepatomegaly have been observed rarely .

There is a genetic predisposition for the occurrence of the hypersensitivity reaction: In patients with the allele HLA-B * 57: 01, the hypersensitivity reaction occurs in up to 80% of cases. Therefore, a genetic test for the presence of the corresponding gene is indicated before starting therapy with abacavir. Regardless of this, abacavir should be discontinued at the first signs of a hypersensitivity reaction.

It appears that there is an increased risk of myocardial infarction in patients at high cardiovascular risk , especially those who have recently started abacavir therapy.

Plasma concentrations can be increased if alcohol is consumed at the same time. There is little interaction with zidovudine or lamivudine . Interactions with the cytochrome P450 system are unlikely.

Resistances

Details are known about the mechanisms of resistance development. Changes in amino acids 65, 74, 115 and 184 of reverse transcriptase are associated with a reduction in sensitivity. Similar nucleosides such as zalcitabine and didanosine are usually less effective against such strains. In order to counteract the development of resistance, the combination in the context of a HAART is absolutely necessary.

Stereoisomerism

Abacavir is chiral and contains two stereogenic centers in the 1- and 4-positions of the cyclopentenyl ring. So there are four stereoisomers : the (1 S , 4 S ) form, the (1 R , 4 R ) form, the (1 R , 4 S ) form and the (1 S , 4 R ) form. Only the (1 S , 4 R ) diastereomer is used as the drug abacavir .

Pharmaceutical information

The water-soluble abacavir hemisulfate (2 abacavir · H ₂ SO ₄ ) is used medicinally . It can be used orally . The succinate as well as the mono- and dichloride are also known.

History

The patent for abacavir was filed in the USA in 1988. The advantages over other products that were on the market at the time were the dosage, which was only necessary twice a day, the independence of taking from meals and the low potential for interaction. In combination therapy, it could be combined with zidovudine and lamivudine. After it had already been approved in the United States in 1998, the manufacturer Glaxo Wellcome was granted approval in the European Union on July 8, 1999 for combination antiretroviral therapy for adults with HIV infection. In Germany it was available from July 15, 1999 under the trade name Ziagen ^® . The combination therapy with Combivir ^® ( azidothymidine + lamivudine ) was the most compact therapy regimen at the time. A major problem was the hypersensitivity syndrome described above. In January 2000 the company Glaxo-Wellcome GmbH & Co. sent a red-hand letter . On November 15, 2000, the FDA approved Glaxo Wellcome for Trizivir ^® (600 mg abacavir + 150 mg lamivudine + 300 mg zidovudine), the first triple combination in antiretroviral therapy. European approval followed two months later in January 2001. Now for the company GlaxoSmithKline plc , which was merged in December 2000. Trizivir ^® has reduced the dosage to taking one tablet twice a day. In October 2001, approval was granted for a pediatric formulation, a banana and strawberry flavored solution, for children aged 3 months to 18 years. In 2002, the once-a-day application for abacavir was released. Another Rote-Hand-Brief in July 2002 indicated a high rate of non-response to therapy with the triple combination of abacavir with tenofovir and lamivudine. This year it was discovered that the occurrence of the hypersensitivity reaction depends on a certain HLA type. If this type is present, the risk of developing a hypersensitivity reaction is increased by a factor of 100. In a Rote-Hand-Brief in November 2008, the company GlaxoSmithKline pointed out the need to test the HLA type before starting therapy.

Trade names

Monopreparations

GlaxoSmithKline : Ziagen (D, A, CH); Generics

Combination preparations

• with lamivudine : Kivexa (D, A, CH); Generics
• with lamivudine and dolutegravir : Triumeq (D, A, CH)
• with lamivudine and zidovudine : Trizivir (D, A, CH)

Web links

• Product information on Ziagen , Kivexa and Trizivir on the website of the European Medicines Agency .
• Antiretrovirals and major drugs in HIV 2012. The book on HIV and AIDS.
• Substance classes, drug overview in HIV 2012. The book on HIV and AIDS.

Individual evidence

1. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals . 14th edition, 2006, p. 1, ISBN 978-0-911910-00-1 .
2. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
3. ↑ ^{a b c} Technical information Ziagen 300 mg film-coated tablets . As of July 2016.
4. ↑ ROTE LISTE 2017, Verlag Rote Liste Service GmbH, Frankfurt am Main, p. 157, ISBN 978-3-946057-10-9 .
5. ↑ Christiane Berg: HIV research: developments and perspectives . In: Pharmaceutical newspaper . GOVI-Verlag, May 25, 1998.
6. ↑ Daniel Rücker: A lot helps a lot - at least as a last resort . In: Pharmaceutical newspaper . GOVI-Verlag, September 21, 1998.
7. ↑ Abacavir approved . In: Pharmaceutical newspaper . GOVI-Verlag, July 19, 1999 ( pharmische-zeitung.de ).
8. ↑ Ulrich Brunner, Eschborn, Brigitte M. Gensthaler: New on the market . In: Pharmaceutical newspaper . August 2, 1999 ( pharmische-zeitung.de ).
9. ↑ Reports from the Drug Commission of the German Pharmacists - Important Safety Information on Hypersensitivity Reaction, Respiratory Symptoms and Ziagen (Abacavir Hemisulfate) . In: Pharmaceutical newspaper . tape 2000 , no. 4 . GOVI-Verlag, January 25, 2000.
10. ↑ Three in one tablet . In: Pharmaceutical newspaper . GOVI-Verlag, November 27, 2000 ( pharmische-zeitung.de ).

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !