Valganciclovir

Valganciclovir

Systematic (IUPAC) name
2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]-3-hydroxypropyl-(2S)-2-amino-3-methylbutanoate
Clinical data
Trade names	Valcyte
AHFS/Drugs.com	monograph
MedlinePlus	a605021
Pregnancy category	US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	60%
Protein binding	1–2%
Metabolism	Hydrolysed to ganciclovir
Biological half-life	4 hours
Excretion	Renal
Identifiers
CAS Number	175865-59-5 N
ATC code	J05AB14 (WHO)
PubChem	CID: 64147
IUPHAR/BPS	4716
DrugBank	DB01610 Y
ChemSpider	57721 Y
UNII	GCU97FKN3R Y
ChEMBL	CHEMBL1201314 N
NIAID ChemDB	032967
Chemical data
Formula	C14H22N6O5
Molecular mass	354.362 g/mol
SMILES O=C(OCC(OCn1c2N\C(=N/C(=O)c2nc1)N)CO)[C@@H](N)C(C)C
InChI InChI=1S/C14H22N6O5/c1-7(2)9(15)13(23)24-4-8(3-21)25-6-20-5-17-10-11(20)18-14(16)19-12(10)22/h5,7-9,21H,3-4,6,15H2,1-2H3,(H3,16,18,19,22)/t8?,9-/m0/s1 Y Key:WPVFJKSGQUFQAP-GKAPJAKFSA-N Y
NY (what is this?)  (verify)

Valganciclovir (Valcyte, manufactured by Hoffmann–La Roche, and also known as Cymeval, Valcyt, Valixa, Darilin, Rovalcyte, Patheon, and Syntex) is an antiviral medication used to treat cytomegalovirus infections. As the L-valyl ester of ganciclovir, it is actually a prodrug for ganciclovir. After oral administration, it is rapidly converted to ganciclovir by intestinal and hepatic esterases.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

Administration

Orally, available in 450 mg tablets. For patients who have received a transplant, the recommended dose is 900 mg once daily, starting within 10 days of transplantation and continuing for 6 months post transplantation. HIV patients might initially need to take the dose 900 mg twice daily for the first 3 weeks.

Pharmacokinetics

1. Oral bioavailability is approximately 60%. Fatty foods significantly increase the bioavailability and the peak level in the serum.
2. It takes about 2 hours to reach maximum concentrations in the serum.
3. Valganciclovir is eliminated as ganciclovir in the urine, with a half-life of about 4 hours in people with normal kidney function.
4. The mechanism of this drug is activation via a viral protein kinase HCMV UL97 and subsequent phosphorylation by cellular kinases. The phosphotransferase enzyme can likewise activate valganciclovir.

Side effects

• Blood: neutropenia, anemia, low platelets. Myelosuppression is one of the main side effects that may limit prolonged use of valganciclovir.
• Gastrointestinal: diarrhea, nausea, vomiting, abdominal pain.
• Central nervous system: fever, headache, insomnia, paresthesia, and peripheral neuropathy.
• Ocular: retinal detachment

Alternative uses

It has been proposed that valganciclovir could be used in the treatment of chronic fatigue syndrome. In an initial, open-label trial, 12 patients with elevated antibody titers to human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) and who had suffered with neurocognitive symptoms and debilitating fatigue consistent with chronic fatigue syndrome were administered valganciclovir for six months. "Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities," accompanied in the same patients by falls in antibody titers to both viruses. The results of a follow-up double-blind, placebo-controlled study of 30 patients were ambiguous: overall scores on the Multidimensional Fatigue Inventory (MFS-20) were nominally higher in valganciclovir-treated patients vs. placebo, but the difference was not statistically significant; moreover, there were no differences in antibody titers between the two groups. However, in a secondary analysis, differences in several specific subscales of the score were significantly different between valganciclovir treatment and placebo.

Continuous treatment of cytomegalovirus infections with valganciclovir in patients with glioblastoma multiforme has shown to increase 2-year survival to 90% in a trial of 25 patients.

In a free preview of a Wednesday, March 4, 2015 online journal article from the New England Journal of Medicine, it was stated that,: "The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time." ... "Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.)."

Price and patent status

Roche's Valcyte is protected by patent. However a generic version manufactured by Japanese-owned Indian company Daiichi-Ranbaxy was found by the District Court of New Jersey, USA not to infringe Roche's patent. In November 2014, FDA approved generics by two manufacturers, Endo and Dr. Reddy's. Endo's generic is already available throughout major pharmacies in the US.

The price of a four-month course of valganciclovir from Roche is about US$8,500 in high-income countries, $6,000 in India. However, the valganciclovir patent was rejected by the Indian Patent Office in 2010, although Roche may appeal the rejection.

References

• Kogelnik AM et al. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. J Clin Virol. 2006;37(S1):S33-S38.
• Paltiel AD et al. Preevaluation of clinical trial data: the case of preemptive cytomegalovirus therapy in patients with human immunodeficiency virus. Clin Infect Dis. 2001;32(5):783-93.
• Pescovitz MD et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother. 2000;44(10):2811-5.
• Reusser P. Antiviral therapy: current options and challenges. Schweiz Med Wochenschr. 2000;130(4):101-12.