Zalcitabine

Zalcitabine

File:Zalcitabine.svg
Systematic (IUPAC) name
4-amino-1-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
Clinical data
Trade names	Hivid (discontinued)
AHFS/Drugs.com	monograph
Pregnancy category	AU: D US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only) US: ℞-only ℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	>80%
Protein binding	<4%
Metabolism	Hepatic
Biological half-life	2 hours
Excretion	Renal (circa 80%)
Identifiers
CAS Number	7481-89-2 Y
ATC code	J05AF03 (WHO)
PubChem	CID: 24066
IUPHAR/BPS	4828
DrugBank	DB00943 Y
ChemSpider	22498 Y
UNII	6L3XT8CB3I Y
KEGG	D00412 Y
ChEBI	CHEBI:10101 Y
ChEMBL	CHEMBL853 Y
NIAID ChemDB	000006
Chemical data
Formula	C9H13N3O3
Molecular mass	211.218 g/mol
SMILES O=C1/N=C(/N)\C=C/N1[C@@H]2O[C@@H](CC2)CO
InChI InChI=1S/C9H13N3O3/c10-7-3-4-12(9(14)11-7)8-2-1-6(5-13)15-8/h3-4,6,8,13H,1-2,5H2,(H2,10,11,14)/t6-,8+/m0/s1 Y Key:WREGKURFCTUGRC-POYBYMJQSA-N Y
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Zalcitabine (2′-3′-dideoxycytidine, ddC), also called dideoxycytidine, is a nucleoside analog reverse transcriptase inhibitor (NARTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

Zalcitabine appears less potent than some other nucleoside RTIs, has an inconvenient three-times daily frequency and is associated with serious adverse events. For these reasons it is now rarely used to treat human immunodeficiency virus (HIV), and it has even been removed from pharmacies entirely in some countries.

History

Zalcitabine was first synthesized in the sixties by Jerome Horwitz and subsequently developed as an anti-HIV agent by Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan at the National Cancer Institute (NCI). Like didanosine, it was then licensed because the NCI may not market or sell drugs. The National Institutes of Health (NIH) thus licensed it to Hoffmann-La Roche.

Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It was approved on June 19, 1992 as a monotherapy and again in 1996 for use in combination with zidovudine (AZT). Using combinations of NRTIs was in practice prior to the second FDA approval and the triple drug combinations with dual NRTIs and a protease inhibitor (PI) were not far off by this time.

The sale and distribution of zalcitabine has been discontinued since December 31, 2006.

Mechanism of action

Zalcitabine is an analog of pyrimidine. It is a derivative of the naturally existing deoxycytidine, made by replacing the hydroxyl group in position 3' with a hydrogen.

It is phosphorylated in T cells and other HIV target cells into its active triphosphate form, ddCTP. This active metabolite works as a substrate for HIV reverse transcriptase, and also by incorporation into the viral DNA, hence terminating the chain elongation due to the missing hydroxyl group. Since zalcitabine is a reverse transcriptase inhibitor it possesses activity only against retroviruses.

Pharmacokinetics

Zalcitabine has a very high oral absorption rate of over 80%. It is predominantly eliminated by the renal route, with a half-life of 2 hours.

Drug interactions

Lamivudine (3TC) significantly inhibits the intracellular phosphorylation of zalcitabine to the active form, and accordingly the drugs should not be administered together.

Additionally, zalcitabine should not be used with other drugs that can cause peripheral neuropathy, such as didanosine and stavudine.

Adverse events

The most common adverse events at the beginning of treatment are nausea and headache. More serious adverse events are peripheral neuropathy, which can occur in up to 33% of patients with advanced disease, oral ulcers, oesophageal ulcers and, rarely, pancreatitis.

Resistance

Resistance to zalcitabine develops infrequently compared with other nRTIs, and generally only occurs at a low level. The most common mutation observed in vivo is T69D, which does not appear to give rise to cross-resistance to other nRTIs; mutations at positions 65, 74, 75, 184 and 215 in the pol gene are observed more rarely.

Specialty drugs

In 1992 dideoxycytidine was listed as a specialty drug.

Further reading

• Yarchoan R, Mitsuya H, Broder S. AIDS therapies. Scientific American 1988;259(4):110-9.
• Harvey Stewart C. in Remington's Pharmaceutical Sciences 18th edition: (ed. Gennard, Alfonso R.) Mack Publishing Company, 1990
• Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3rd edition. Pearson Professional Ltd, 1995.
• Mitsuya H, Broder S. Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy virus-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides. Proc Natl Acad Sci USA 1986;83:1911-5.
• Yarchoan R, Perno CF, Thomas RV, et al. Phase I studies of 2',3'-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet 1988;1:76-81.
• Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990;249:1533-44.
• NIH Bio and Oral History of Samuel Broder describing the development of anti-HIV drugs: http://aidshistory.nih.gov/transcripts/bios/Samuel_Broder.html
• NIH Bio and Oral History of Robert Yarchoan describing the development of anti-HIV drugs: http://aidshistory.nih.gov/transcripts/bios/Robert_Yarchoan.html
• Moyle G. A re-evaluation of zalcitabine. Expert Opin Investig Drugs 1998;7:451-62