Zalcitabine

Zalcitabine (2′-3′-dideoxycytidine, ddC), also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) 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
Clinical data
Trade namesHivid (discontinued)
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: D
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability>80%
Protein binding<4%
MetabolismHepatic
Elimination half-life2 hours
ExcretionRenal (circa 80%)
Identifiers
IUPAC name
  • 4-amino-1-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.149.677
Chemical and physical data
FormulaC9H13N3O3
Molar mass211.221 g·mol−1
3D model (JSmol)
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
  (verify)

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.[1]

History

Zalcitabine was first synthesized in the 1960s by Jerome Horwitz[2][3] 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.[4]

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.[5]

Drug interactions

Lamivudine (3TC) significantly inhibits the intracellular phosphorylation of zalcitabine to the active form, and accordingly the drugs should not be administered together.[5]

Additionally, zalcitabine should not be used with other drugs that can cause peripheral neuropathy, such as didanosine and stavudine.[5]

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.[5]

Resistance

Resistance to zalcitabine develops infrequently compared with other nRTIs, and generally only occurs at a low level.[6] 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.[5][6]

Specialty drugs

In 1992 dideoxycytidine was listed as a specialty drug.[7]

Sources
  1. "zalcitabine (CHEBI:10101)". www.ebi.ac.uk. Retrieved 2021-01-18.
  2. Horwitz JR, Chua J, Da Rooge MA, Noel M, Klundt IL (January 1966). "Nucleosides. IX. The formation of 2',2'-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction". The Journal of Organic Chemistry. American Chemical Society (ACS). 31 (1): 205–11. doi:10.1021/jo01339a045. PMID 5900814.
  3. Oral account of the history of AZT, d4T and ddC by Jerome Horwitz and Hiroaki Mitsuya in the documentary film I am alive today - History of an AIDS drug.
  4. "HIVID (zalcitabine) tablets" (PDF). M.D./alert. U.S. Food and Drug Administration. June 2006. Archived from the original (PDF) on 3 February 2012.
  5. "HIVID (zalcitabine) tablets. Product information" (PDF). Roche. September 2002. Archived from the original (PDF) on 16 September 2009.
  6. Moyle GJ (August 1996). "Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences". Drugs. Springer Nature. 52 (2): 168–85. doi:10.2165/00003495-199652020-00002. PMID 8841736. S2CID 27709969.
  7. Töglhofer W (1992). "[New, in Austria registered specialty drugs. Hivid (2',3'-dideoxycytidine; ddC)]". Wiener Klinische Wochenschrift. 104 (12): 363–7. PMID 1353278.

Further reading
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